Solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole

ABSTRACT

The present disclosure provides solid forms of (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole, compositions thereof, and methods of making and using the same.

RELATED APPLICATIONS

The present application is a continuation of International PatentApplication No. PCT/US20/27710, filed Apr. 10, 2020, which claimspriority to U.S. Provisional Patent Application No. 62/832,519, filedApr. 11, 2019, the entire contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Scatter factor (SF; also known as hepatocyte growth factor (HGF), andhereinafter referred to and abbreviated as HGF/SF) is a pleiotropicgrowth factor that stimulates cell growth, cell motility, morphogenesisand angiogenesis. HGF/SF is produced as an inactive monomer (˜100 kadam)which is proteolytically converted to its active form. Active HGF/SF isa heparin-binding heterodimeric protein composed of a 62 kDa a chain anda 34 kDa 0 chain. HGF/SF is a potent mitogen for parenchymal liver,epithelial and endothelial cells (Matsumoto, K, and Nakamura, T., 1997,Hepatocyte growth factor (HGF) as a tissue organizer for organogenesisand regeneration. Biochem. Biophys. Res. Commun. 239, 639-44; Boros, P.and Miller, C. M., 1995, Hepatocyte growth factor: a multifunctionalcytokine. Lancet 345, 293-5). It stimulates the growth of endothelialcells and also acts as a survival factor against endothelial cell death(Morishita, R, Nakamura, S, Nakamura, Y, Aoki, M, Moriguchi, A, Kida, I,Yo, Y, Matsumoto, K, Nakamura, T, Higaki, J, Ogihara, T, 1997, Potentialrole of an endothelium-specific growth factor, hepatocyte growth factor,on endothelial damage in diabetes. Diabetes 46:138-42). HGF/SFsynthesized and secreted by vascular smooth muscle cells stimulatesendothelial cells to proliferate, migrate and differentiate intocapillary-like tubes in vitro (Grant, D. S, Kleinman, H. K., Goldberg,I. D., Bhargava, M. M., Nickoloff, B. J., Kinsella, J. L., Polverini,P., Rosen, E. M., 1993, Scatter factor induces blood vessel formation invivo. Proc. Natl. Acad. Sci. USA 90:1937-41; Morishita, R., Nakamura,S., Hayashi, S., Taniyama, Y., Moriguchi, A., Nagano, T., Taiji, M.,Noguchi, H., Takeshita, S., Matsumoto, K., Nakamura, T., Higaki, J.,Ogihara, T., 1999, Therapeutic angiogenesis induced by human recombinanthepatocyte growth factor in rabbit hind limb ischemia model as cytokinesupplement therapy. Hypertension 33:1379-84). HGF/SF-containing implantsin mouse subcutaneous tissue and rat cornea induce growth of new bloodvessels from surrounding tissue. HGF/SF protein is expressed at sites ofneovascularization including in tumors (Jeffers, M., Rong, S., Woude, G.F., 1996, Hepatocyte growth factor/scatter factor-Met signaling intumorigenicity and invasion/metastasis. J. Mol. Med. 74:505-13;Moriyama, T., Kataoka, H., Koono, M., Wakisaka, S., 1999, Expression ofhepatocyte growth factor/scatter factor and its receptor c-met in braintumors: evidence for a role in progression of astrocytic tumors Int. J.Mol. Med. 3:531-6). These findings suggest that HGF/SF plays asignificant role in the formation and repair of blood vessels underphysiologic and pathologic conditions.

All citations in the present application are incorporated herein byreference in their entireties. The citation of any reference hereinshould not be construed as an admission that such reference is availableas “Prior Art” to the instant application.

SUMMARY

Polymorphs, solvates and salts of various drugs have been described inthe literature as imparting novel properties to the drugs. Organic smalldrug molecules have a tendency to self-assemble into various polymorphicforms depending on the environment that drives the self-assembly. Heat-and solvent-mediated effects can also lead to changes that transform onepolymorphic form into another.

Identifying which polymorphic form or forms are the most stable undereach condition of interest, and the processes that lead to changes inthe polymorphic form, is warranted for design of the drug manufacturingprocess in order to ensure that a final product is in its preferredpolymorphic form. Different polymorphic forms of an activepharmaceutical ingredient (API) can lead to changes in a drug'ssolubility, dissolution rate, pharmacokinetics, and, ultimately, itsbioavailability and efficacy in patients.

Novel solid forms of the present invention, and compositions thereof,are useful in the treatment and/or prevention of conditions or diseasesin which HGF/SF activity is desirable. In general, these solid forms,and pharmaceutically acceptable compositions thereof, are useful fortreating or lessening the severity of a variety of diseases or disordersas described in detail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an X-Ray Powder Diffraction (XRPD) pattern of solid FormA.

FIG. 2 provides Differential Scanning Calorimeter (DSC) thermogram ofsolid Form A.

FIG. 3 provides another DSC thermogram of solid Form A.

FIG. 4 provides a further DSC thermogram of solid Form A.

FIG. 5 provides a Thermogravimetric Analysis (TGA) curve of solid FormA.

FIG. 6 provides another TGA curve of solid Form A.

FIG. 7 provides a further TGA curve of solid Form A.

FIG. 8 provides an X-Ray Powder Diffraction (XRPD) pattern of a mixtureof solid Form A and solid Form C.

FIG. 9 provides a Differential Scanning Calorimeter (DSC) thermogram ofa mixture of solid Form A and solid Form C.

FIG. 10 provides a Thermogravimetric Analysis (TGA) curve of a mixtureof solid Form A and solid Form C.

FIG. 11 provides an X-Ray Powder Diffraction (XRPD) pattern of a mixtureof solid Form A and solid Form D.

FIG. 12 provides a Differential Scanning Calorimeter (DSC) thermogram ofa mixture of solid Form A and solid Form D.

FIG. 13 provides a Thermogravimetric Analysis (TGA) curve of a mixtureof solid Form A and solid Form D.

FIG. 14 provides XRPD pattern of Compound 1 Lot I.

FIG. 15 provides TGA curve of Compound 1 Lot I.

FIG. 16 provides DSC thermogram of Compound 1 Lot I.

FIG. 17 provides XRPD pattern of Compound 1 Form A calculated fromsingle crystal X-ray diffraction data.

FIG. 18 provides XRPD pattern of Compound 1 Form A.

FIG. 19 provides TGA curve of Compound 1 Form A.

FIG. 20 provides DSC thermogram of Compound 1 Form A.

FIG. 21 provides a comparison of XRPD patterns of Compound 1 Lot I andCompound 1 Form A.

FIG. 22 provides XRPD pattern of Compound 1 Form C calculated fromsingle crystal X-ray diffraction data.

FIG. 23 provides XRPD pattern of Compound 1 Form C.

FIG. 24 provides TGA curve of Compound 1 Form C.

FIG. 25 provides DSC thermogram of Compound 1 Form C.

FIG. 26 provides XRPD pattern of Compound 1 Form D calculated fromsingle crystal X-ray diffraction data.

FIG. 27 provides XRPD pattern of Compound 1 Form D.

FIG. 28 provides TGA curve of Compound 1 Form D.

FIG. 29 provides DSC thermogram of Compound 1 Form D.

FIG. 30 provides dynamic vapor sorption (DVS) of Compound 1 Form A.

FIG. 31 provides dynamic vapor sorption (DVS) of Compound 1 Form C.

FIG. 32 provides dynamic vapor sorption (DVS) of Compound 1 Form D.

FIG. 33 provides XRPD patterns collected on the materials recoveredafter DVS (a: Form A (calculated); b: Form A after DVS; c: Form C afterDVS; d: Form D after DVS).

FIG. 34 provides XRPD results of slurry experiments (a: Form A(calculated); b: Form A after slurrying in IPA at RT for 3 days; c: FormC after slurrying in IPA at RT for 3 days; d: Form D after slurrying inIPA at RT for 3 days).

FIG. 35 provides XRPD results of competitive slurry experiments (a: FormA (calculated); b: Form A+C after slurrying in IPA at RT for 3 days; c:Form A+D after slurrying in IPA at RT for 3 days; d: Form C+D afterslurrying in IPA at RT for 3 days).

FIG. 36 provides XRPD results of stability studies of Form A (a: Form A(calculated); b: Form A after storage for 4 weeks at at 2° C.; c: Form Aafter storage for 4 weeks at 25° C./60% RH; d: Form A after storage for4 weeks at 40° C./75% RH).

FIG. 37 provides XRPD results of stability studies of Form C (a: Form A(calculated); b: Form C (calculated); c: Form C after storage for 4weeks at at 2° C.; d: Form C after storage for 4 weeks at 25° C./60% RH;e: Form C after storage for 4 weeks at 40° C./75% RH).

FIG. 38 provides XRPD results of stability studies of Form D (a: Form A(calculated); b: Form D (calculated); c: Form D after storage for 4weeks at at 2° C.; d: Form D after storage for 4 weeks at 25° C./60% RH;e: Form D after storage for 4 weeks at 40° C./75% RH).

FIG. 39 provides XRPD results of UV stability studies of Form A (a: FormA (calculated); b: Form A after storage for 1 week at 365 nm; c: Form Aafter storage for 1 week at 254 nm).

FIG. 40 provides XRPD results of UV stability studies of Form C (a: FormC (calculated); b: Form C after storage for 1 week at 365 nm; c: Form Cafter storage for 1 week at 254 nm).

FIG. 41 provides XRPD results of UV stability studies of Form D (a: FormD (calculated); b: Form D after storage for 1 week at 365 nm; c: Form Dafter storage for 1 week at 254 nm).

FIG. 42A provides single crystal X-ray crystallography of Compound 1Form A. N and S atoms are labeled; unlabeled non-hydrogen atoms arecarbon.

FIG. 42B provides single crystal X-ray crystallography of Compound 1Form C. N, S, and O atoms are labeled; unlabeled non-hydrogen atoms arecarbon.

FIG. 42C provides single crystal X-ray crystallography of Compound 1Form D. N, S, and O atoms are labeled; unlabeled non-hydrogen atoms arecarbon.

DETAILED DESCRIPTION

PCT patent application PCT/US2003/040917, filed Dec. 19, 2003 andpublished as WO2004/058721 on Jul. 15, 2004, the entirety of which ishereby incorporated by reference, describes certain compounds that actas HGF/SF mimetics. Such compounds include Compound 1:

A synthesis of Compound 1, (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole, isdescribed in detail in Example 7 of WO2004/058721. Those skilled in theart will appreciate that Compound 1 has a structure that can exist invarious tautomeric forms, including(E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole and(E)-5-[2-(2-thienyl)vinyl]-1H-pyrazole, or any mixture thereof.Moreover, those skilled in the art, reading the present disclosure willappreciate that, in many embodiments, teachings described herein are notlimited to any particular tautomeric form. Accordingly, the structuredepicted above for Compound 1 is meant to include all tautomeric formsof Compound 1, including (E)-3-[2-(2-thienyl)vinyl]-1H-pyrazole and(E)-5-[2-(2-thienyl)vinyl]-1H-pyrazole. Compound 1 can also be referredto as (E)-3(5)-[2-(2-thienyl)vinyl]-1H-pyrazole.

It is desirable to provide a solid form of Compound 1 that, as comparedto amorphous Compound 1, imparts characteristics such as improvedsolubility, stability, storability, ease of purification duringmanufacture, ease of handling and/or ease of formulation. Accordingly,the present disclosure provides several solid forms of Compound 1.

Solid Forms of Compound 1

Compound 1 can exist in an amorphous solid form or in a crystallinesolid form, or in a mixture thereof. Crystalline solid forms can existin one or more unique forms, which can be solvates, heterosolvates,hydrates, or unsolvated forms. All such forms are contemplated by thepresent disclosure.

In some embodiments, this disclosure provides one or more polymorphicsolid forms of Compound 1. As used herein, the term “polymorph” refersto the ability of a compound to exist in one or more different crystalstructures. For example, one or more polymorphs may vary inpharmaceutically relevant physical properties between one form andanother, for example solubility, stability, and hygroscopicity.

In some embodiments, the present disclosure provides an anhydrous (i.e.,unsolvated) polymorphic form of Compound 1.

In some embodiments, Compound 1 is provided as a solvate orheterosolvate. As used herein, the term “solvate” refers to a solid formwith a stoichiometric amount of one or more solvents (e.g., water,ethylene glycol, propylene glycol, etc.) incorporated into the crystalstructure. For example, a solvated or heterosolvated polymorph cancomprise 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc. equivalentsindependently of one or more solvents incorporated into the crystallattice.

In some embodiments, Compound 1 is provided as a hydrate. As usedherein, the term “hydrate” refers to a solid form with a stoichiometricamount of water incorporated into the crystal structure. For example, ahydrated polymorph can comprise 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, 2.0, etc.equivalents of water incorporated into the crystal lattice.

In some embodiments, Compound 1 is provided as a hydrate and/or asolvate or heterosolvate.

In some embodiments, a crystalline solid form of Compound 1 is provided.

In some embodiments, the present disclosure provides a solvate form ofCompound 1. In some embodiments, a solvate form of Compound 1 is anethylene glycol solvate. In some embodiments, a solvate form of Compound1 is a propylene glycol solvate.

In some embodiments, this disclosure provides a composition comprising acrystalline solid form of Compound 1. In some embodiments, the presentdisclosure provides a composition comprising a mixture of two or morecrystalline solid forms of Compound 1. In some embodiments, the presentdisclosure provides a composition comprising a mixture of one or morecrystalline solid forms of Compound 1 and amorphous Compound 1. In someembodiments, a composition is substantially free of amorphousCompound 1. As used herein, the term “substantially free of amorphousCompound 1” means that a composition contains no significant amount ofamorphous Compound 1. In some embodiments, a composition comprises atleast about 90% by weight of crystalline Compound 1. In someembodiments, a composition comprises at least about 95% by weight ofcrystalline Compound 1. In some embodiments, a composition comprises atleast about 97%, about 98%, or about 99% by weight of crystallineCompound 1.

Compound 1 can exist in at least three distinct crystalline solid forms,designated herein as Form A, Form C, and Form D.

As used herein, the term “about,” when used in reference to a degree2-theta value refers to the stated value±0.2 degree 2-theta. In someembodiments, “about” refers to the stated value±0.1 degree 2-theta.

Form A

In some embodiments, a crystalline solid form of Compound 1 is Form A.In some embodiments, Form A of Compound 1 is unsolvated (e.g.,anhydrous).

In some embodiments, Form A is characterized by one or more peaks in itsXRPD pattern selected from those at about 8.64, about 11.04, about17.34, about 25.06, and about 25.70 degrees 2-theta. In someembodiments, Form A is characterized by two or more peaks in its XRPDpattern selected from those at about 8.64, about 11.04, about 17.34,about 25.06, and about 25.70 degrees 2-theta. In some embodiments, FormA is characterized by three or more peaks in its XRPD pattern selectedfrom those at about 8.64, about 11.04, about 17.34, about 25.06, andabout 25.70 degrees 2-theta.

In some embodiments, Form A is characterized by peaks in its XRPDpattern at about 8.64, about 11.04, about 17.34, about 25.06, and about25.70 degrees 2-theta. In some embodiments, Form A is characterized bypeaks in its XRPD pattern at about 8.64, about 11.04, about 17.34, about25.06, and about 25.70 degrees 2-theta, corresponding to d-spacing ofabout 10.22, about 8.01, about 5.11, about 3.55, and about 3.46angstroms.

In some embodiments, Form A is characterized by substantially all of thepeaks (degrees 2-theta) in its XRPD pattern, optionally corresponding tod-spacing (angstroms), at about:

2θ (°) d-spacing (Å) 8.64 10.27 11.04 8.01 11.67 7.57 16.06 5.51 17.345.11 18.27 4.85 18.69 4.74 19.49 4.55 20.66 4.30 21.09 4.21 21.70 4.0922.10 4.02 22.76 3.90 23.46 3.79 23.74 3.74 25.06 3.55 25.70 3.46 26.123.41 26.32 3.38 27.64 3.23 27.78 3.21 28.31 3.15 28.49 3.13 29.04 3.0729.95 2.98 31.59 2.83 31.82 2.81 37.25 2.77 33.22 2.69 34.21 2.62 34.422.60 35.08 2.56 35.53 2.52 36.33 2.47 36.70 2.45 37.16 2.42 37.65 2.3939.02 2.31 39.60 2.27 39.81 2.26

In some embodiments, Form A is characterized by one or more of thefollowing:

-   -   (i) an XRPD pattern substantially similar to that depicted in        FIG. 17 and/or FIG. 18,    -   (ii) a TGA pattern substantially similar to that depicted in        FIG. 19;    -   (iii) a DSC pattern substantially similar to that depicted in        FIG. 20; and    -   (iv) a melting point of about 116.42° C.

In some embodiments, Form A is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by two or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by three or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.064degrees 2-theta±0.2.

In some embodiments, Form A is characterized by four or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by five or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by six or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by seven or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by eight or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by nine or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by ten or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 15.61,17.22, 17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern selected from those at 8.60, 15.61, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61 and 17.22 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61 and 26.1 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61 and 35.06 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 17.22 and 26.1 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 17.22 and 35.06 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 17.22, 26.1, and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61, 26.1, and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61, 17.22, and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61, 17.22, and 26.1 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 15.61, 17.22, 26.1, and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 17.30 and 17.35 degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 8.60, 17.30, and 17.35 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 8.60, 17.22, 17.30 and 17.35 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 8.60, 17.22, 17.30, 17.35 and 21.04degrees 2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern at 8.60, 17.22, 17.30, 17.35, 21.04 and 23.41degrees 2-theta±0.2.

In some embodiments, Form A is characterized by an XRPD pattern withsubstantially the same peaks (degrees 2-theta±0.2), optionallycorresponding to d-spacing (angstroms±0.2) and/or relative intensity (%)of:

Degrees d-spacing Relative 2-Theta ± 0.2 (Å) intensity (%) 8.60 10.2723.1 15.61 5.67 1.0 17.22 5.15 19.3 17.30 5.12 100 17.35 5.11 58.2 21.044.22 4.4 22.05 4.03 1.5 23.41 3.80 2.6 24.97 3.56 2.4 25.63 3.47 2.126.10 3.41 1.8 35.06 2.56 2.3

In some embodiments, Form A is characterized by one or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by two or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by three or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.064degrees 2-theta±0.2.

In some embodiments, Form A is characterized by four or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by five or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by six or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by seven or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by eight or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by nine or more peaks inits X-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by ten or more peaks in itsX-ray powder diffraction pattern selected from those at 8.60, 17.22,17.30, 17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by peaks in its X-raypowder diffraction pattern selected from those at 8.60, 17.22, 17.30,17.35, 21.04, 22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees2-theta±0.2.

In some embodiments, Form A is characterized by an XRPD pattern withsubstantially the same peaks (degrees 2-theta±0.2), optionallycorresponding to d-spacing (angstroms±0.2) and/or relative intensity (%)of:

Degrees d-spacing Relative 2-Theta ± 0.2 (Å) intensity (%) 8.60 10.2773.1 17.22 5.15 19.3 17.30 5.12 100 17.35 5.11 58.2 21.04 4.22 4.4 22.054.03 1.5 23.41 3.80 2.6 24.97 3.56 2.4 25.63 3.47 2.1 26.10 3.41 1.835.06 2.56 7.3

In some embodiments, Form A of Compound 1 has one or more of thefollowing characteristics:

(i) an XRPD pattern substantially similar to that depicted in FIG. 1;

(ii) a DSC pattern substantially similar to that depicted in any one ofFIG. 2, FIG. 3, or FIG. 4;

(iii) a TGA pattern substantially similar to that depicted in any one ofFIG. 5, FIG. 6, or FIG. 7; and

(iv) a melting point of about 115-120° C.

Form C

In some embodiments, a crystalline solid form of Compound 1 is Form C.In some embodiments, Form C of Compound 1 is a propylene glycol solvate.In some embodiments, Form C of Compound 1 is a propylene glycol solvate,wherein the ratio of Compound 1 to propylene glycol is about 2:1.

In some embodiments, Form C is characterized by one or more peaks in itsXRPD pattern selected from those at about 11.88, about 17.50, about19.08, about 21.28, and about 23.07 degrees 2-theta. In someembodiments, Form C is characterized by two or more peaks in its XRPDpattern selected from those at about 11.88, about 17.50, about 19.08,about 21.28, and about 23.07 degrees 2-theta. In some embodiments, FormC is characterized by three or more peaks in its XRPD pattern selectedfrom those at about 11.88, about 17.50, about 19.08, about 21.28, andabout 23.07 degrees 2-theta.

In some embodiments, Form C is characterized by peaks in its XRPDpattern at about 11.88, about 17.50, about 19.08, about 21.28, and about23.07 degrees 2-theta. In some embodiments, Form C is characterized bypeaks in its XRPD pattern at about 11.88, about 17.50, about 19.08,about 21.28, and about 23.07 degrees 2-theta, corresponding to d-spacingof about 7.44, about 5.06, about 4.65, about 4.17, and about 3.85angstroms.

In some embodiments, Form C is characterized by substantially all of thepeaks (degrees 2-theta) in its XRPD pattern, optionally corresponding tod-spacing (angstroms), at about:

2θ (°) d-spacing (Å) 6.20 14.24 11.88 7.44 12.41 7.13 14.79 5.99 15.725.63 17.50 5.06 17.78 4.98 19.08 4.65 19.36 4.58 21.28 4.17 21.89 4.0623.07 3.85 23.69 3.75 23.92 3.72 24.70 3.60 24.90 3.57 25.50 3.49 25.713.46 26.28 3.39 27.74 3.21 28.13 3.17 29.10 3.07 29.31 3.04 29.55 3.0230.51 2.93 31.15 2.87 31.76 2.82 32.93 2.72 33.19 2.70 33.36 2.68 34.632.59 35.05 2.56 35.40 2.53 35.90 2.50 36.20 2.48 36.60 2.45 37.57 2.3937.69 2.38 38.05 2.36 38.54 7.33 38.80 2.32 39.05 2.30 39.46 2.28 39.822.26

In some embodiments, Form C of Compound 1 has one or more of thefollowing characteristics:

(i) an XRPD pattern substantially similar to that depicted in FIG. 22and/or FIG. 23;

(ii) a TGA pattern substantially similar to that depicted in any one ofFIG. 24;

(iii) a DSC pattern substantially similar to that depicted in any one ofFIG. 25; and

(iv) a melting point of about 75.22° C.

Form D

In some embodiments, a crystalline solid form of Compound 1 is Form D.In some embodiments, Form D of Compound 1 is an ethylene glycol solvate.In some embodiments, Form D of Compound 1 is an ethylene glycol solvate,wherein the ratio of Compound 1 to ethylene glycol is about 2:1.

In some embodiments, Form D is characterized by one or more peaks in itsXRPD pattern selected from those at about 12.28, about 15.10, about18.06, about 21.58, and about 23.88 degrees 2-theta. In someembodiments, Form D is characterized by two or more peaks in its XRPDpattern selected from those at about 12.28, about 15.10, about 18.06,about 21.58, and about 23.88 degrees 2-theta. In some embodiments, FormD is characterized by three or more peaks in its XRPD pattern selectedfrom those at about 12.28, about 15.10, about 18.06, about 21.58, andabout 23.88 degrees 2-theta.

In some embodiments, Form D is characterized by peaks in its XRPDpattern at about 12.28, about 15.10, about 18.06, about 21.58, and about23.88 degrees 2-theta. In some embodiments, Form D is characterized bypeaks in its XRPD pattern at about 12.28, about 15.10, about 18.06,about 21.58, and about 23.88 degrees 2-theta, corresponding to d-spacingof about 7.20, about 5.86, about 4.91, about 4.11, and about 3.72angstroms.

In some embodiments, Form D is characterized by substantially all of thepeaks (degrees 2-theta) in its XRPD pattern, optionally corresponding tod-spacing (angstroms), at about:

2θ (°) d-spacing (Å) 6.19 14.28 12.28 7.20 12.38 7.14 15.10 5.86 15.245.81 16.17 5.48 17.60 5.03 18.06 4.91 18.63 4.76 19.11 4.64 19.44 4.5620.35 4.36 21.58 4.11 21.95 4.05 22.55 3.94 23.88 3.72 24.70 3.60 24.883.58 25.57 3.48 25.76 3.46 26.07 3.42 26.33 3.38 26.50 3.36 26.75 3.3326.99 3.30 27.25 3.27 28.51 3.13 28.72 3.11 29.96 2.98 30.10 2.97 30.262.95 30.47 2.93 30.62 2.92 30.75 2.90 31.27 2.86 31.57 2.83 31.83 2.8131.97 2.80 32.38 2.76 32.67 2.74 33.61 2.66 33.82 2.65 34.84 2.57 35.782.51 36.02 2.49 36.36 2.47 36.53 2.46 36.66 2.45 37.10 2.42 37.44 2.4037.81 2.38 38.38 2.34 38.72 2.32 39.24 2.29 39.78 2.26

In some embodiments, Form D of Compound 1 has one or more of thefollowing characteristics:

(i) an XRPD pattern substantially similar to that depicted in FIG. 26and/or FIG. 27;

(ii) a TGA pattern substantially similar to that depicted in any one ofFIG. 28;

(iii) a DSC pattern substantially similar to that depicted in any one ofFIG. 29; and

(iv) a melting point of about 76.95° C.

Mixtures of Compound 1 Solid Forms

In some embodiments, a composition comprising a mixture of solid formsof Compound 1 is provided. In some such embodiments, a providedcomposition comprises a mixture of Form A and at least one additionalsolid form of Compound 1. In some embodiments, a provided compositioncomprises a mixture of Form A and Form C. In some embodiments, aprovided composition comprises a mixture of Form A and Form D.

In some embodiments, this disclosure provides a mixture comprising FormsA and C in a ratio of between about 98:2 and about 95:5. In oneembodiment, this invention provides a mixture comprising Forms A and Cin a ratio of between about 95:5 and about 90:10. In one embodiment,this disclosure provides a mixture comprising Forms A and C in a ratioof between about 90:10 and about 85:15. In one embodiment, thisdisclosure provides a mixture comprising Forms A and C in a ratio ofbetween about 85:15 and about 80:20. In one embodiment, this disclosureprovides a mixture comprising Forms A and C in a ratio of about 50:50.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by one or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by two or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by three or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by four or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by five or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by six or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by seven or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by eight or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by nine or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by ten or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by eleven or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by twelve or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by thirteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by fourteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by fifteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by sixteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by seventeen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by eighteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by nineteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by twenty or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by twenty-one or more peaks in its X-ray powderdiffraction pattern selected from those at 8.58, 10.97, 11.81, 14.72,15.65, 17.32, 17.41, 17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97,23.60, 24.92, 25.59, 26.20, 27.65, 30.42, 31.07, and 35.33 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by peaks in its X-ray powder diffraction patternselected from those at 8.58, 10.97, 11.81, 14.72, 15.65, 17.32, 17.41,17.70, 18.61, 19.02, 19.27, 21.20, 22.09, 22.97, 23.60, 24.92, 25.59,26.20, 27.65, 30.42, 31.07, and 35.33 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having two peaks in its X-ray powderdiffraction pattern selected from among 14.72, 19.02, 22.97, 24.92,27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having three peaks in its X-ray powderdiffraction pattern selected from among 14.72, 19.02, 22.97, 24.92,27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having four peaks in its X-ray powderdiffraction pattern selected from among 14.72, 19.02, 22.97, 24.92,27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having five peaks in its X-ray powderdiffraction pattern selected from among 14.72, 19.02, 22.97, 24.92,27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having six peaks in its X-ray powderdiffraction pattern selected from among 14.72, 19.02, 22.97, 24.92,27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having one peak in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having two peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having three peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having four peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having five peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having six peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having seven peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having eight peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having nine peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having ten peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having eleven peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having twelve peaks in its X-ray powderdiffraction pattern selected from among 15.65, 17.7, 19.27, 21.2, 23.6,35.33, 14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having the following peaks in its X-raypowder diffraction pattern at 15.65, 17.7, 19.27, 21.2, 23.6, 35.33,14.72, 19.02, 22.97, 24.92, 27.65, 30.42 and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 21.20 and 22.97 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 17.32, 21.20, and 22.97 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 17.32, 19.02, 21.20, and 22.97 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 17.32, 17.41, 19.02, 21.20, and 22.97 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 17.32, 17.41, 19.02, 21.20, 22.97, and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, and 31.07 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, 26.20, and 31.07degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, 26.20, 27.65, and31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 8.58, 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, 26.20, 27.65,and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 8.58, 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, 25.59, 26.20,27.65, and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by having peaks in its X-ray powder diffractionpattern at 8.58, 10.97, 11.81, 17.32, 17.41, 19.02, 21.20, 22.97, 25.59,26.20, 27.65, and 31.07 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm C is characterized by an XRPD pattern with substantially the samepeaks (degrees 2-theta±0.2), optionally corresponding to d-spacing(angstroms±0.2) and/or relative intensity (%) of:

Degrees d-spacing Relative 2-Theta ± 0.2 (Å) intensity (%) 8.58 10.304.8 10.97 8.06 3.9 11.81 7.49 9.2 14.72 6.01 3.2 15.65 5.66 3.1 17.325.12 18.5 17.41 5.09 14.4 17.70 5.00 7.5 18.61 4.76 2.3 19.02 4.66 17.319.27 4.60 2.7 21.20 4.19 100 22.09 4.02 3.6 22.97 3.87 22.2 23.60 3.773.1 24.92 3.57 3.2 25.59 3.48 4.0 26.20 3.40 6.9 27.65 3.22 5.2 30.422.94 2.5 31.07 2.88 10.2 35.33 2.54 2.3

In some embodiments, a composition comprising a mixture of Form A andForm C of Compound 1 has one or more of the following characteristics:

(i) an XRPD pattern substantially similar to that depicted in FIG. 8;

(ii) a DSC pattern substantially similar to that depicted in any one ofFIG. 9;

(iii) a TGA pattern substantially similar to that depicted in any one ofFIG. 10; or

(iv) a melting point including metastable forms of about 68.7° C., 99.5°C., and 209.4° C.

In some embodiments, this disclosure provides a mixture comprising FormsA and D in a ratio of between about 2:98 and about 5:95. In oneembodiment, this disclosure provides a mixture comprising Forms A and Din a ratio of between about 5:95 and about 10:90. In one embodiment,this disclosure provides a mixture comprising Forms A and D in a ratioof between about 10:90 and about 15:85. In one embodiment, thisdisclosure provides a mixture comprising Forms A and D in a ratio ofbetween about 15:85 and about 20:80. In one embodiment, this disclosureprovides a mixture comprising Forms A, and D in a ratio of about 50:50.

In some embodiments, this disclosure provides a mixture comprising FormsA and D in a ratio of between about 98:2 and about 95:5. In oneembodiment, this invention provides a mixture comprising Forms A and Din a ratio of between about 95:5 and about 90:10. In one embodiment,this disclosure provides a mixture comprising Forms A and D in a ratioof between about 90:10 and about 85:15. In one embodiment, thisdisclosure provides a mixture comprising Forms A and D in a ratio ofbetween about 85:15 and about 80:20.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by one or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by two or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by three or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by four or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by five or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by six or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by seven or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eight or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nine or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by ten or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eleven or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twelve or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by thirteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by fourteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by fifteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by sixteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by seventeen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eighteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nineteen or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-one or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-two or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-three or more peaks in its X-raypowder diffraction pattern selected from those at 8.69, 9.99, 11.08,12.34, 15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60,22.22, 22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98,30.60, 31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-four or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-five or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-six or more peaks in its X-ray powderdiffraction pattern selected from those at 8.69, 9.99, 11.08, 12.34,15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22,22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60,31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-seven or more peaks in its X-raypowder diffraction pattern selected from those at 8.69, 9.99, 11.08,12.34, 15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60,22.22, 22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98,30.60, 31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-eight or more peaks in its X-raypowder diffraction pattern selected from those at 8.69, 9.99, 11.08,12.34, 15.12, 16.15, 17.38, 17.62, 18.08, 18.67, 19.47, 21.13, 21.60,22.22, 22.76, 23.50, 23.91, 25.04, 25.69, 26.49, 28.36, 28.52, 29.98,30.60, 31.84, 33.83, 34.44, 35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternselected from those at 8.69, 9.99, 11.08, 12.34, 15.12, 16.15, 17.38,17.62, 18.08, 18.67, 19.47, 21.13, 21.60, 22.22, 22.76, 23.50, 23.91,25.04, 25.69, 26.49, 28.36, 28.52, 29.98, 30.60, 31.84, 33.83, 34.44,35.74, and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by two peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by three peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by four peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by five peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by six peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by seven peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eight peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nine peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nine peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by ten peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eleven peaks in its X-ray powder diffractionpattern selected from among 9.99, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 9.99, 12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44,35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by two peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by three peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by four peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by five peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by six peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by seven peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eight peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nine peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by ten peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eleven peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twelve peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by thirteen peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by fourteen peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by fifteen peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by sixteen peaks in its X-ray powder diffractionpattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67, 19.47,21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84, 12.34,15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and 38.77degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by seventeen peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by eighteen peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by nineteen peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D Form D is characterized by twenty peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-one peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-two peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-three peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-four peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by twenty-five peaks in its X-ray powderdiffraction pattern selected from among 8.69, 9.99, 11.08, 17.62, 18.67,19.47, 21.13, 22.22, 22.76, 23.5, 25.69, 28.36, 28.52, 29.98, 31.84,12.34, 15.12, 16.15, 18.08, 23.91, 26.49, 30.6, 33.83, 34.44, 35.74 and38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 9.99, 11.08, 17.62, 18.67, 19.47, 21.13, 22.22, 22.76, 23.5,25.69, 28.36, 28.52, 29.98, 31.84, 12.34, 15.12, 16.15, 18.08, 23.91,26.49, 30.6, 33.83, 34.44, 35.74 and 38.77 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 17.38 and 21.60 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 17.38, 21.60, and 22.22 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 11.08, 17.38, 21.60, and 22.22 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 11.08, 17.38, 21.60, 22.22, and 23.91 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 11.08, 17.38, 21.13, 21.60, 22.22, and 23.91 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 17.38, 21.13, 21.60, 22.22, and 23.91 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 17.38, 21.13, 21.60, 22.22, 23.91, and 25.69 degrees2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 17.38, 21.13, 21.60, 22.22, 23.91, 25.04, and 25.69degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 17.38, 17.62, 21.13, 21.60, 22.22, 23.91, 25.04, and25.69 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 12.34, 17.38, 17.62, 21.13, 21.60, 22.22, 23.91, 25.04,and 25.69 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 12.34, 17.38, 17.62, 21.13, 21.60, 22.22, 23.91, 25.04,25.69, and 28.52 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 12.34, 17.38, 17.62, 21.13, 21.60, 22.22, 23.50, 23.91,25.04, 25.69, and 28.52 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by peaks in its X-ray powder diffraction patternat 8.69, 11.08, 12.34, 17.38, 17.62, 21.13, 21.60, 22.22, 23.50, 23.91,25.04, 25.69, and 28.52, 31.84 degrees 2-theta±0.2.

In some embodiments, a composition comprising a mixture of Form A andForm D is characterized by an XRPD pattern with substantially the samepeaks (degrees 2-theta±0.2), optionally corresponding to d-spacing(angstroms±0.2) and/or relative intensity (%) of:

Degrees d-spacing Relative 2-Theta ± 0.2 (Å) intensity (%) 8.69 10.1724.3 9.99 8.85 2.0 11.08 7.98 60.8 12.34 7.17 11.0 15.12 5.85 4.1 16.155.48 2.7 17.38 5.10 100 17.62 5.03 11.5 18.08 4.90 4.9 18.67 4.75 6.119.47 4.55 5.9 21.13 4.20 34.3 21.60 4.11 84.7 27.22 4.00 74.5 22.763.90 2.0 23.50 3.78 7.6 23.91 3.72 34.4 25.04 3.55 11.7 25.69 3.46 16.826.49 3.36 5.5 28.36 3.14 5.0 28.52 3.13 8.2 29.98 2.98 5.5 30.60 2.925.5 31.84 2.81 7.0 33.83 2.65 2.6 34.44 2.60 2.0 35.74 7.51 2.8 38.772.32 3.0

In some embodiments, a composition comprising a mixture of Form A andForm D of Compound 1 has one or more of the following characteristics:

(I) an XRPD pattern substantially similar to that depicted in FIG. 11;

(ii) a DSC pattern substantially similar to that depicted in any one ofFIG. 12;

(iii) a TGA pattern substantially similar to that depicted in any one ofFIG. 13; or

(iv) a melting point including metastable forms of about 90.0° C.,111.2° C., 123.5° C. and 223.0° C.

Methods of Providing Solid Forms of Compound 1

The present disclosure provides methods of providing (e.g., making)various solid forms of Compound 1, as well as compositions comprisingmixtures of Compound 1 in one or more solid forms and/or an amorphousform.

In some embodiments, solid forms of Compound 1 can be prepared bydissolving Compound 1 (e.g., amorphous Compound 1, crystalline Compound1, or a mixture thereof) in a suitable solvent and then causing Compound1 to return to the solid phase. In some embodiments, solid forms ofCompound 1 are prepared by combining amorphous and/or crystallineCompound 1 in a suitable solvent under suitable conditions and isolatinga solid form of Compound 1. In some embodiments, solid forms of Compound1 are prepared by dissolving amorphous and/or crystalline Compound 1 inat least one organic solvent at a temperature of between about −60° C.and about 60° C. (e.g., between about 25° C. and about 45° C.) and thensubjecting the mixture to conditions suitable for crystallization,thereby obtaining the solid form of Compound 1. In some suchembodiments, conditions suitable for crystallization comprise coolingthe mixture to a temperature between about −60° C. and about 30° C.

In some embodiments, conditions suitable for crystallization comprisecooling a mixture to a temperature of about 5° C. In some embodiments,conditions suitable for crystallization comprise cooling a mixture to atemperature of about −20° C. In some embodiments, conditions suitablefor crystallization comprise cooling a mixture to a temperature of about20° C. In some embodiments, conditions suitable for crystallizationcomprise cooling a mixture to a temperature of between about 20° C. andabout 60° C. In some embodiments, conditions suitable forcrystallization comprise cooling a mixture to a temperature of about−10° C. to about 0° C. In some embodiments, conditions suitable forcrystallization comprise cooling a mixture to a temperature of about 0°C. to about 5° C. In some embodiments, conditions suitable forcrystallization comprise cooling a mixture to a temperature of about−10° C. to about −20° C.

In some embodiments, solid forms of Compound 1 are prepared bycrystallization from a suitable solvent composition comprising one ormore solvents. In some embodiments, a suitable solvent compositioncomprises two solvents in a 1:1 v/v ratio. In some embodiments, asuitable solvent composition comprises two solvents in a 1:2 v/v ratio.In some embodiments, a suitable solvent composition comprises twosolvents in a 1:3 v/v ratio. In some embodiments, a suitable solventcomposition comprises two solvents in a 1:4 v/v ratio. In someembodiments, a suitable solvent composition comprises two solvents in a1:5 v/v ratio. In some embodiments, a suitable solvent compositioncomprises two solvents in a 1:6 v/v ratio. In some embodiments, asuitable solvent composition comprises two solvents in a 1:7 v/v ratio.In some embodiments, a suitable solvent composition comprises twosolvents in a 1:8 v/v ratio. In some embodiments, a suitable solventcomposition comprises two solvents in a 1:9 v/v ratio. In someembodiments, a suitable solvent composition comprises two solvents in a1:10 v/v ratio. In some embodiments, a suitable solvent compositioncomprises two solvents in a 1:11 v/v ratio. In some embodiments, asuitable solvent composition comprises two solvents in a 1:12 v/v ratio.In some embodiments, a suitable solvent composition comprises twosolvents in a 1:13 v/v ratio. In some embodiments, a suitable solventcomposition comprises two solvents in a 1:14 v/v ratio. In someembodiments, a suitable solvent composition comprises two solvents in a1:15 v/v ratio. In some embodiments, a suitable solvent compositioncomprises two solvents in a 1:16 v/v ratio. In some embodiments, asuitable solvent composition comprises two solvents in a 1:17 v/v ratio.

In some embodiments, solids forms of Compound 1 are prepared byslurrying in a suitable solvent or solvent composition at a suitabletemperature. In some such embodiments, solid forms of Compound 1 arethen isolated via filtration.

In some embodiments, Form A of Compound 1 is prepared from a suitablesolvent selected from: methanol, ethanol, acetone, methyl ethyl ketone,methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate,tetrahydrofuran (THF), ethanol/acetic acid, acetone/water, THF/water,dioxane/water, methanol/water, acetonitrile/water, 3-methyl-1-butanol,2-methyl-1-propanol, isopropanol, isobutyl acetate, isopropyl acetate,toluene, n-butyl acetate, dichloromethane (DCM), methyl tert-butylether, dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetic acid,hexane, heptane, formic acid, 2-ethoxyethanol, 1-butanol, 2-butanol,ethyl ether, ethanol/water, DMSO/water, and toluene/heptane.

In some embodiments, Form A of Compound 1 is prepared from ethanol/water9:1 v/v. In some embodiments, Form A of Compound 1 is prepared fromacetone/water 9:1 v/v. In some embodiments, Form A of Compound 1 isprepared from THF/water 9:1 v/v. In some embodiments, Form A of Compound1 is prepared from 1,4-dioxane/water 9:1 v/v. In some embodiments, FormA of Compound 1 is prepared from acetonitrile/water 9:1 v/v. In someembodiments, Form A of Compound 1 is prepared from DMSO/water 9:1 v/v.In some embodiments, Form A of Compound 1 is prepared from ethanol/water9:1 v/v.

In some embodiments, Form A of Compound 1 is prepared by dissolvingCompound 1 in methanol at a suitable temperature (e.g., about 50° C.);and/or cooling the resulting solution to a suitable temperature (e.g.,about 25° C.); and/or allowing for slow evaporation of the resultingsolution for a suitable period of time so that Form A of Compound 1forms.

In some embodiments, Form A of Compound 1 is prepared by slurryingcrystalline Compound 1 in methanol at a suitable temperature (e.g.,about 25° C.) for a suitable period of time (e.g., about two days).

In some embodiments, Form C of Compound 1 is prepared by dissolvingCompound 1 in a solvent composition comprising propylene glycol andmethyl isobutyl ketone (e.g., in a ratio of about 1:6) at a suitabletemperature (e.g., about 50); and/or cooling the resulting solution to asuitable temperature (e.g., about −27° C.) for a suitable period of time(e.g., about two days).

In some embodiments, Form D of Compound 1 is prepared by dissolvingCompound 1 in a solvent composition comprising ethylene glycol andmethyl isobutyl ketone (e.g., in a ratio of about 1:6) at a suitabletemperature (e.g., about 50° C.); and/or cooling the resulting solutionto a suitable temperature (e.g., about −27° C.) for a suitable period oftime (e.g., about two days).

In some embodiments, a composition comprising a mixture of Form A andForm C of Compound 1 is prepared from propylene glycol/methyl isobutylketone. In some embodiments, a composition comprising a mixture of FormA and Form C of Compound 1 is prepared from propylene glycol/methylisobutyl ketone 1:11 v/v.

In some embodiments, a composition comprising a mixture of Form A andForm D of Compound 1 is prepared from ethylene glycol/methyl isobutylketone. In some embodiments, a composition comprising a mixture of FormA and Form D of Compound 1 is prepared from ethylene glycol/methylisobutyl ketone 1:11 v/v.

In some embodiments, a solid form of Compound 1 is obtained by a processdescribed in Example 2.

In some embodiments, solid forms of Compound 1 precipitate out ofsolution. In some embodiments, solid forms of Compound 1 crystallizefrom solution. In some embodiments, solid forms of Compound 1precipitate out of solution after removal of part or all of the solvent.In some embodiments, solid forms of Compound 1 precipitate out ofsolution after crash cooling. In some embodiments, solid forms ofCompound 1 precipitate out of solution after addition of ananti-solvent.

In some embodiments, solid forms of Compound 1 are optionally isolated.In some embodiments, solid forms of Compound 1 are dried by vacuum atroom temperature, followed by gradually increasing the temperature. Insome embodiments, solid forms of Compound 1 are collected by filtration.

In some embodiments, a solid form of Compound 1 is prepared byconverting one solid form into another solid form.

Pharmaceutical Compositions

The present disclosure also provides pharmaceutical compositionscomprising a solid form of Compound 1, and a pharmaceutically acceptablecarrier. In some embodiments, a pharmaceutical composition comprises atherapeutically effective amount of an active ingredient (e.g., a solidform of Compound 1) together with a pharmaceutically acceptable carrier.Certain liquid (e.g., for intravenous or intraperitoneal administration)and solid (e.g., for oral administration) formulations of Compound 1have been described. See, for example, PCT Application No.PCT/US2009/004014, filed Jul. 9, 2009 and published as WO 2010/005580 onJan. 14, 2010, the entirety of which is hereby incorporated byreference.

As used herein, the phrase “therapeutically effective amount” refers toan amount that produces a desired effect for which it is administered.In some embodiments, the term refers to an amount that is sufficient,when administered to a population suffering from or susceptible to adisease, disorder, and/or condition in accordance with a therapeuticdosing regimen, to treat the disease, disorder, and/or condition. Insome embodiments, a therapeutically effective amount is one that reducesthe incidence and/or severity of, stabilizes one or more characteristicsof, and/or delays onset of, one or more symptoms of the disease,disorder, and/or condition. Those of ordinary skill in the art willappreciate that the term “therapeutically effective amount” does not infact require successful treatment be achieved in a particularindividual. Rather, a therapeutically effective amount may be thatamount that provides a particular desired pharmacological response in asignificant number of subjects when administered to patients in need ofsuch treatment. In some embodiments, reference to a therapeuticallyeffective amount may be a reference to an amount as measured in one ormore specific tissues (e.g., a tissue affected by the disease, disorderor condition) or fluids (e.g., blood, saliva, serum, sweat, tears,urine, etc.). Those of ordinary skill in the art will appreciate that,in some embodiments, a therapeutically effective amount may beformulated and/or administered in a single dose. In some embodiments, atherapeutically effective amount may be formulated and/or administeredin a plurality of doses, for example, as part of a dosing regimen.

In some embodiments, a pharmaceutical composition comprises Form A ofCompound 1 and a pharmaceutically acceptable carrier.

In some embodiments, a pharmaceutical composition comprises Form C ofCompound 1 and a pharmaceutically acceptable carrier.

In some embodiments, a pharmaceutical composition comprises a Form D ofCompound 1 and a pharmaceutically acceptable carrier.

In some embodiments, this disclosure provides pharmaceuticalcompositions comprising a mixture of one or more solid forms of Compound1 and/or amorphous Compound 1 and a pharmaceutically acceptable carrier.

Pharmaceutical compositions described herein can be administered to asubject by any known method, such as orally, parenterally, perineurally,transmucosally, transdermally, intramuscularly, intravenously,intradermally, subcutaneously, intraperitoneally, intraventricularly,intracranially or intratumorally. In some embodiments, providedpharmaceutical compositions are suitable for injection.

In some embodiments, provided pharmaceutical compositions areadministered intravenously, and are thus formulated in a form suitablefor intravenous administration, i.e. as a liquid preparation. In someembodiments, provided liquid pharmaceutical compositions (e.g., thosesuitable for intravenous administration) are prepared from a solid formdescribed herein. In some embodiments, a solid form described herein hasdesirable properties for preparing a liquid formulation, such as,increased solubility.

In some embodiments, a liquid pharmaceutical composition comprises about0.8 to about 10 mg/mL of Compound 1. In some embodiments, a liquidpharmaceutical composition comprises about 0.25% to about 0.75% (w/v) ofCompound 1. In some embodiments, a liquid pharmaceutical compositioncomprises about 0.5% (w/v) of Compound 1.

In some embodiments, a liquid pharmaceutical composition is preparedfrom about 0.8 mg to about 10 mg of a solid form of Compound 1 permilliliter of liquid used in the composition.

In some embodiments, a liquid pharmaceutical composition compriseswater. In some embodiments, a liquid pharmaceutical compositioncomprises saline solution, buffer solution, or buffered-saline solution.In some embodiments, a liquid pharmaceutical composition comprisesphosphate-buffered saline solution. In some embodiments,phosphate-buffered saline solution is about 30% to about 50% (v/v) of aliquid pharmaceutical composition. In some embodiments,phosphate-buffered saline solution is about 40% (v/v) of a liquidpharmaceutical composition.

In some embodiments, a liquid pharmaceutical composition has a pHbetween about pH 5 and about pH 9. In some embodiments, a liquidpharmaceutical composition has a pH between about pH 6 and about pH 8.In some embodiments, a liquid pharmaceutical composition is pH 7.4.

In some embodiments, a liquid pharmaceutical composition comprisespolyethylene glycol. In some embodiments, polyethylene glycol (e.g.,polyethylene glycol 300) is about 40% to about 60% (v/v) of thepharmaceutical composition. In some embodiments, polyethylene glycol(e.g., polyethylene glycol 300) is about 50% (v/v) of the pharmaceuticalcomposition. In some embodiments, polyethylene glycol is polyethyleneglycol 200. In some embodiments, polyethylene glycol is polyethyleneglycol 300. In some embodiments, polyethylene glycol is polyethyleneglycol 400.

In some embodiments, a liquid pharmaceutical composition comprisespolysorbate. In some embodiments, polysorbate (e.g., polysorbate 80) isabout 5% to about 15% (v/v) of the pharmaceutical composition. In someembodiments, polysorbate (e.g., polysorbate 80) is about 10% (v/v) ofthe pharmaceutical composition. In some embodiments, polysorbate ispolysorbate 20. In some embodiments, polysorbate is polysorbate 80.

In some embodiments, a liquid pharmaceutical composition comprisespolyethylene glycol (e.g., polyethylene glycol 300), polysorbate (e.g.,polysorbate 80), or a combination thereof. In some embodiments, a liquidpharmaceutical composition comprises about 50% (v/v) polyethylene glycol300 and about 10% (v/v) polysorbate 80.

The present disclosure also provides methods of preparing providedliquid pharmaceutical compositions comprising Compound 1. In someembodiments, a method comprises steps of (i) providing one or more solidforms of Compound 1; and (ii) formulating the one or more solid forms ofCompound 1 with suitable excipients to provide a liquid pharmaceuticalcomposition. In some embodiments, a step of formulating comprisescombining one or more solid forms of Compound 1 with aqueous bufferedsaline, polyethylene glycol (e.g., polyethylene glycol 300) andpolysorbate (e.g., polysorbate 80). In some embodiments, a step offormulating comprising combining one or more solid forms of Compound 1with suitable excipients so that the liquid formulation comprises about50% (v/v) polyethylene glycol 300 and about 10% (v/v) polysorbate 80 inaqueous-buffered saline.

In some embodiments, provided methods of preparing provided liquidpharmaceutical compositions further comprise a step of sterilizing thecomposition and/or one or more individual components of the composition(e.g., prior to combining with the other components).

In some embodiments, provided pharmaceutical compositions areadministered orally, and are thus formulated in a form suitable for oraladministration, i.e. as a solid preparation. Suitable solid oralformulations include tablets, capsules, pills, granules, pellets and thelike. In some embodiments, provided solid forms are formulated in acapsule. In some such embodiments, a composition comprises, in additionto Compound 1 and the pharmaceutically acceptable carrier, a hardgelatin capsule.

Oral formulations containing any one of, or mixtures of, the presentsolid forms can comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, or lozenges. In someembodiments, capsules comprise Form A, Form C, or Form D, or anycombination thereof, of Compound 1. Capsules or tablets of a particularcrystalline form may also be combined with mixtures of other activecompounds and/or inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc.

Tablet formulations can be made by conventional compression, wetgranulation, or dry granulation methods and utilize pharmaceuticallyacceptable diluents (fillers), binding agents, lubricants,disintegrants, suspending or stabilizing agents, including, but notlimited to, magnesium stearate, stearic acid, talc, sodium laurylsulfate, microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations, in some embodiments, utilize standard delay ortime release formulations or spansules.

Example excipient systems suitable for preparing formulations ofprovided solid forms include one or more fillers, disintegrants, andlubricants.

A filler component can be any filler component known in the artincluding, but not limited to, lactose, microcrystalline cellulose,sucrose, mannitol, calcium phosphate, calcium carbonate, powderedcellulose, maltodextrin, sorbitol, starch, or xylitol.

Disintegrants suitable for use in provided formulations can be selectedfrom those known in the art, including pregelatinized starch and sodiumstarch glycolate. Other useful disintegrants include croscarmellosesodium, crospovidone, starch, alginic acid, sodium alginate, clays (e.g.veegum or xanthan gum), cellulose floc, ion exchange resins, oreffervescent systems, such as those utilizing food acids (such as citricacid, tartaric acid, malic acid, fumaric acid, lactic acid, adipic acid,ascorbic acid, aspartic acid, erythorbic acid, glutamic acid, andsuccinic acid) and an alkaline carbonate component (such as sodiumbicarbonate, calcium carbonate, magnesium carbonate, potassiumcarbonate, ammonium carbonate, etc.). Disintegrant(s) useful herein canmake up from about 4% to about 40% of the composition by weight,preferably from about 15% to about 35%, more preferably from about 20%to about 35%.

Provided pharmaceutical formulations can also contain an antioxidant ora mixture of antioxidants, such as ascorbic acid. Other antioxidantswhich can be used include sodium ascorbate and ascorbyl palmitate,preferably in conjunction with an amount of ascorbic acid. An examplerange for the antioxidant(s) is from about 0.5% to about 15% by weight,most preferably from about 0.5% to about 5% by weight.

In some embodiments, an active pharmacological agent(s) comprises fromabout 0.5% to about 20%, by weight, of the final composition, or in someembodiments, from about 1% to about 5%, and a coating or capsulecomprises up to about 8%, by weight, of a final composition.

Formulations described herein can be used in an uncoated ornon-encapsulated solid form. In some embodiments, pharmacologicalcompositions are optionally coated with a film coating, for example,comprising from about 0.3% to about 8% by weight of the overallcomposition. Film coatings useful with provided formulations are knownin the art and generally consist of a polymer (usually a cellulosic typeof polymer), a colorant and a plasticizer. Additional ingredients suchas wetting agents, sugars, flavors, oils and lubricants may be includedin film coating formulations to impart certain characteristics to thefilm coat. Compositions and formulations provided herein may also becombined and processed as a solid, then placed in a capsule form, suchas a gelatin capsule.

In some embodiments, an active compound can be delivered in a vesicle,in particular a liposome (see Langer, Science 249:1527-1533 (1990);Treat et al., in Liposomes in the Therapy of Infectious Disease andCancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365(1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).

Pharmaceutically acceptable carriers or diluents are well known to thoseskilled in the art. A carrier or diluent may be a solid carrier ordiluent for solid formulations. Solid carriers and diluents include, butare not limited to, a gum, a starch (e.g. corn starch, pregeletanizedstarch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), acellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g.polymethylacrylate), calcium carbonate, magnesium oxide, talc, ormixtures thereof.

In addition, provided compositions may further comprise binders (e.g.acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone),disintegrating agents (e.g. cornstarch, potato starch, alginic acid,silicon dioxide, croscarmelose sodium, crospovidone, guar gum, sodiumstarch glycolate), buffers (e.g., Tris-HCl, acetate, phosphate) ofvarious pH and ionic strength, additives such as albumin or gelatin toprevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80,Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.sodium lauryl sulfate), permeation enhancers, solubilizing agents (e.g.,glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid,sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g.hydroxypropyl cellulose, hyroxypropylmethyl cellulose), viscosityincreasing agents (e.g. carbomer, colloidal silicon dioxide, ethylcellulose, guar gum), sweeteners (e.g. aspartame, citric acid),preservatives (e.g., Thimerosal, benzyl alcohol, parabens), lubricants(e.g. stearic acid, magnesium stearate, polyethylene glycol, sodiumlauryl sulfate), flow-aids (e.g. colloidal silicon dioxide),plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers(e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymercoatings (e.g., poloxamers or poloxamines), coating and film formingagents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/oradjuvants.

In some embodiments, pharmaceutical compositions provided herein arecontrolled release compositions, i.e. compositions in which the compoundis released over a period of time after administration. In someembodiments, provided compositions are immediate release compositions,i.e. a composition in which all of the compound is released immediatelyafter administration.

In some embodiments, pharmaceutical compositions can be delivered in acontrolled release system. For example, an agent may be administeredusing liposomes, or other modes of oral administration.

Provided compositions may also include incorporation of an activematerial into or onto particulate preparations of polymeric compoundssuch as polylactic acid, polyglycolic acid, hydrogels, etc, or ontoliposomes, microemulsions, micelles, unilamellar or multilamellarvesicles, erythrocyte ghosts, or spheroplasts. Such compositions willinfluence the physical state, solubility, stability, rate of in vivorelease, and rate of in vivo clearance. Preparation of solidpharmaceutical compositions is well understood in the art, for exampleby mixing, granulating, or tablet-forming processes. An activetherapeutic ingredient is often mixed with excipients which arepharmaceutically acceptable and compatible with the active ingredient.For oral administration, compounds or their physiologically toleratedderivatives such as salts, esters, N-oxides, and the like are mixed withadditives customary for this purpose, such as vehicles, stabilizers, orinert diluents, and converted by customary methods into suitable formsfor administration, such as tablets, coated tablets, hard or softgelatin capsules, aqueous, alcoholic or oily solutions.

Uses of Compound 1 and Pharmaceutical Compositions Thereof

Compound 1 (e.g., solid forms of Compound 1) or a pharmaceuticalcomposition thereof is useful for modulating HGF/SF activity in apatient or a biological sample. In some embodiments, Compound 1 (e.g.,solid forms of Compound 1) or a pharmaceutical composition thereof isuseful for providing antifibrotic and antiapoptotic activities. Compound1 is a mimic of HGF/SF and is useful in the treatment of any disease,disorder or condition in which prophylactic and/or therapeuticadministration of HGF/SF would be useful.

The present disclosure provides methods comprising administering atherapeutically effective amount of one or more solid forms of Compound1 to a subject in need thereof.

In some embodiments, the present disclosure provides methods comprising(i) formulating one or more solid forms of Compound 1 to provide apharmaceutical composition: and (ii) administering the pharmaceuticalcomposition to a subject in need thereof.

In some embodiments, the present disclosure provides methods comprisingadministering a pharmaceutical composition comprising Compound 1 to asubject in need thereof, wherein the pharmaceutical composition wasobtained by formulating one or more solid forms of Compound 1 withsuitable excipients.

The present disclosure also provides methods for the use of solid formsof Compound 1, or a pharmaceutical composition thereof, for treating orlessening the severity of a disease or disorder associated with HGF/SFactivity or amenable to treatment by modulating HGF/SF activity.

In some embodiments, the present disclosure provides a method fortreating or lessening the severity of a disease or disorder selectedfrom fibrotic liver disease, hepatic ischemia-reperfusion injury,cerebral infarction, ischemic heart disease, renal disease and lung(pulmonary) fibrosis.

In some embodiments, a method is for treating or lessening the severityof a disease or disorder selected from liver fibrosis associated withhepatitis C, hepatitis B, delta hepatitis, chronic alcoholism,non-alcoholic steatohepatitis, extrahepatic obstructions (stones in thebile duct), cholangiopathies (primary biliary cirrhosis and sclerosingcholangitis), autoimmune liver disease, and inherited metabolicdisorders (Wilson's disease, hemochromatosis, and alpha-1 antitrypsindeficiency); damaged and/or ischemic organs, transplants or grafts;ischemia/reperfusion injury; stroke; cerebrovascular disease; myocardialischemia; atherosclerosis; renal failure; renal fibrosis and idiopathicpulmonary fibrosis.

In some embodiments, the present disclosure provides a method fortreating wounds (e.g., accelerating healing of wounds); promotingvascularization of a damaged and/or ischemic organ, transplant or graft;ameliorating ischemia/reperfusion injury in the brain, heart, liver,kidney, and other tissues and organs; normalizing myocardial perfusionas a consequence of chronic cardiac ischemia or myocardial infarction;increasing development of collateral vessel development after vascularocclusion or to ischemic tissues or organs; or treating a disease orcondition selected from fibrotic diseases, hepatic disease includingfibrosis and cirrhosis, lung fibrosis, radiocontrast nephropathy,fibrosis secondary to renal obstruction, renal trauma andtransplantation, renal failure secondary to chronic diabetes and/orhypertension, and/or diabetes mellitus.

In some embodiments, solid forms of Compound 1, or a pharmaceuticalcomposition thereof, are useful for treatment of various demyelinatingdiseases and traumatic diseases of the central nervous system, such asspinal cold injury, traumatic brain injury, multiple sclerosis andvarious hereditary neurodegenerative diseases, such as, but not limitedto, leukodystrophies including metachromatic leukodystrophy, Refsum'sdisease, adrenoleukodystrophy, Krabbe's disease, phenylketonuria,Canavan disease, Pelizaeus-Merzbacher disease and Alexander's disease.

In some embodiments, solid forms of Compound 1 are useful for treatmentof a chronic obstructive pulmonary disease such as emphysema, orsecondary effects of tobacco abuse or smoking, chronic bronchitis,asthma, cystic fibrosis, alpha-1 antitrypsin deficiency, bronchiectasis,and some forms of bullous lung diseases.

In some embodiments, solid forms of Compound 1 are useful for treatmentof fibrotic diseases of connective tissue, such as, but not limited to,scleroderma, systemic sclerosis, generalized scleroderma, limitedscleroderma and post-surgical adhesions.

In some embodiments, solid forms of Compound 1 are useful for treatmentof muscular dystrophy, amyotrophic lateral sclerosis or chronic heartfailure.

In some embodiments, the present disclosure provides a method oftreating or ameliorating a renal disease, condition or disorder. In someembodiments, a renal disease, condition, or disorder is selected fromrenal trauma, renal transplant, renal failure, or renal fibrosis.

In some embodiments, the present disclosure provides a method ofreducing severity of delayed graft function in a patient that hasreceived a kidney transplant, the method comprising administering to thepatient a solid form of Compound 1, or a pharmaceutical compositionthereof. In some embodiments, a patient has received a deceased donorkidney. In some embodiments, a patient has received a live donor kidney.Reduced severity of delayed graft function can be assessed by one ormore of the following criteria:

(i) the number of days a patient remains dialysis dependent;

(ii) estimated creatinine clearance or renal function; and/or

(iii) urine output.

In some embodiments, a patient has not previously undergone a kidneytransplant. In some embodiments, a patient has not previously received adonor kidney. In some embodiments, a patient has not previously receiveda deceased donor kidney. In some embodiments, a patient has notpreviously received a live donor kidney.

In some embodiments, a patient has poor renal function after undergoinga kidney transplant. In some embodiments, a patient has poor renalfunction in the first 12, 24, 36, or 48 hours after undergoing a kidneytransplant. In some embodiments, a patient has poor renal function inthe first 24 hours after undergoing a kidney transplant. In someembodiments, poor renal function is evidenced by an average urine outputof less than 50 mL per hour over any 8 consecutive hours.

In some embodiments, a patient requires dialysis within the first 1, 2,3, 4, 5, 6, or 7 days after undergoing a kidney transplant.

In some embodiments, the present disclosure provides a method ofpreventing acute kidney injury after cardiac surgery involvingcardiopulmonary bypass, the method comprising administering to a patienta solid form of Compound 1, or a pharmaceutical composition thereof.

In some embodiments, a patient has undergone a non-emergent cardiacsurgical procedure selected from (i) coronary artery bypass graft(CABG), (ii) aortic valve replacement or repair with or without aorticroot repair, (iii) mitral, tricuspid, or pulmonic valve replacement orrepair, (iv) combined replacement of several cardiac valves, (v) CABGwith aortic, mitral, tricuspid, or pulmonic valve replacement or repair,or (vi) CABG with combined cardiac valve replacement or repair.

In some embodiments, a patient has one or more of the following riskfactors:

(i) estimated glomerular filtration rate (eGFR) of ≥20 and <30mL/min/1.73 m2;

(ii) estimated glomerular filtration rate (eGFR) of ≥30 and <60mL/min/1.73 m2;

(iii) estimated glomerular filtration rate (eGFR) of ≥60 mL/min/1.73 m2;

(iv) combined valve and coronary surgery;

(v) previous cardiac surgery with sternotomy;

(vi) left ventricular ejection fraction (LVEF) <35% by invasive ornoninvasive diagnostic cardiac imaging within 90 days prior to surgery;

(vii) diabetes mellitus requiring insulin treatment;

(viii) non-insulin-requiring diabetes with documented presence of atleast moderate (+2) proteinuria on urine analysis;

(ix) documented to be NYHA Class III or IV within 1 year prior tosurgery; and/or

(x) 75 years old or greater.

In some embodiments, a patient has presented for the non-emergentcardiac surgical procedure without prior evidence of active renalinjury, as defined to be no acute rise in serum creatinine >0.3 mg/dLand/or no 50% increase in serum creatinine between the time of screeningand surgery.

Exemplary Embodiments

The following numbered embodiments, while non-limiting, are exemplary ofcertain aspects of the disclosure:

1. A solid form of Compound 1:

2. The solid form of embodiment 1, wherein the solid form iscrystalline.3. The solid form of embodiment 2, wherein Compound 1 a solvate, aheterosolvate, a hydrate, or an unsolvated form.4. The solid form of embodiment 2, wherein Compound 1 is an unsolvatedform.5. The solid form of embodiment 2 or 3, wherein the solid form ischaracterized by one or more peaks in its X-ray powder diffractionpattern selected from those at 8.60, 15.61, 17.22, 17.30, 17.35, 21.04,22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees 2-theta±0.2.6. The solid form of embodiment 5, wherein the solid form ischaracterized by two or more peaks in its X-ray powder diffractionpattern selected from those at 8.60, 15.61, 17.22, 17.30, 17.35, 21.04,22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees 2-theta±0.2.7. The solid form of embodiment 6, wherein the solid form ischaracterized by three or more peaks in its X-ray powder diffractionpattern selected from those at 8.60, 15.61, 17.22, 17.30, 17.35, 21.04,22.05, 23.41, 24.97, 25.63, 26.10 and 35.06 degrees 2-theta±0.2.8. The solid form of any one of embodiments 3-7, wherein the solid formis characterized by having peaks in its X-ray powder diffraction patternat 17.30 and 17.35 degrees 2-theta±0.2.9. The solid form of any one of embodiments 3-8, wherein the solid formis characterized by having peaks in its X-ray powder diffraction patternat 8.60, 17.30, and 17.35 degrees 2-theta±0.2.10. The solid form of any one of embodiments 3-9, wherein the solid formis characterized by having the following peaks in its X-ray powderdiffraction pattern (degrees 2-theta±0.2):

Degrees 2-Theta 8.60 15.61 17.22 17.30 17.35 21.04 22.05 23.41 24.9725.63 26.10 35.0611. The solid form of any one of embodiments 3-10, wherein the solidform is characterized by having the following peaks (degrees2-theta±0.2), corresponding to the following d-spacing (angstroms±0.2),in its X-ray powder diffraction pattern:

Degrees d-spacing 2-Theta (Å) 8.60 10.27 15.61 5.67 17.30 5.12 17.355.11 21.04 4.22 22.05 4.03 23.41 3.80 24.97 3.56 25.63 3.47 26.10 3.4135.06 2.5612. The solid form of any one of embodiments 3-11, wherein the solidform is Form A.13. A composition comprising the solid form of any one of the precedingembodiments.14. The composition of embodiment 13, wherein the composition comprisesat least about 90% by weight crystalline Compound 1.15. The composition of embodiment 14, wherein the composition comprisesat least about 95% by weight crystalline Compound 1.16. The composition of embodiment 15, wherein the composition issubstantially free of amorphous Compound 1.17. A pharmaceutical composition comprising the solid form of any one ofthe preceding embodiments.18. A pharmaceutical composition prepared from a solid form of any oneof the preceding embodiments.19. A method for mimicking HGF/SF activity in a patient, comprising thestep of administering to the patient the solid form of any one ofembodiments 1-12, the composition of any one of embodiment 13-16, or thepharmaceutical composition of embodiment 17 or 18.20. A method for treating a disease or disorder associated with HGF/SFactivity or amenable to treatment by modulating HGF/SF activity,comprising the step of administering to the patient the solid form ofany one of embodiments 1-12, the composition of any one of embodiment13-16, or the pharmaceutical composition of embodiment 17 or 18.21. The method of embodiment 20, wherein the disease or disorder isselected from fibrotic liver disease, hepatic ischemia-reperfusioninjury, cerebral infarction, ischemic heart disease, renal disease, lungfibrosis, liver fibrosis associated with hepatitis C, hepatitis B, deltahepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions, cholangiopathies, autoimmune liver disease,Wilson's disease, hemochromatosis, alpha-1 antitrypsin deficiency,damaged and/or ischemic organs, transplants or grafts,ischemia/reperfusion injury, stroke, cerebrovascular disease, myocardialischemia, atherosclerosis, renal failure, renal fibrosis, idiopathicpulmonary fibrosis, wounds, ischemia/reperfusion injury in the brain,heart, liver, kidney, and other tissues and organs, myocardial perfusionas a consequence of chronic cardiac ischemia or myocardial infarction,fibrotic diseases, hepatic disease including fibrosis and cirrhosis,radiocontrast nephropathy, fibrosis secondary to renal obstruction,renal trauma, renal failure secondary to chronic diabetes and/orhypertension, diabetes mellitus, demyelinating diseases, traumaticdiseases of the central nervous system, spinal cold injury, traumaticbrain injury, multiple sclerosis, hereditary neurodegenerative diseases,chronic obstructive pulmonary disease, fibrotic diseases of connectivetissue, muscular dystrophy, amyotrophic lateral sclerosis or chronicheart failure.22. The method of embodiment 21, wherein the disease or disorder isselected from fibrotic liver disease, hepatic ischemia-reperfusioninjury, cerebral infarction, ischemic heart disease, renal disease orlung fibrosis.23. The method of embodiment 21, wherein the disease or disorder isselected from liver fibrosis associated with hepatitis C, hepatitis B,delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions, cholangiopathies, autoimmune liver disease,Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiency,damaged and/or ischemic organs, transplants or grafts,ischemia/reperfusion injury, stroke, cerebrovascular disease, myocardialischemia, atherosclerosis, renal failure, renal fibrosis, or idiopathicpulmonary fibrosis.24. The method of embodiment 21, wherein the disease or disorder isselected from demyelinating diseases, traumatic diseases of the centralnervous system, spinal cold injury, traumatic brain injury, multiplesclerosis, and hereditary neurodegenerative diseases.25. The method of embodiment 24, wherein the hereditaryneurodegenerative diseases are selected from leukodystrophies includingmetachromatic leukodystrophy, Refsum's disease, adrenoleukodystrophy,Krabbe's disease, phenylketonuria, Canavan disease, Pelizaeus-Merzbacherdisease and Alexander's disease.26. The method of embodiment 21, wherein the chronic obstructivepulmonary disease is selected from emphysema, chronic bronchitis,asthma, cystic fibrosis, alpha-1 antitrypsin deficiency, bronchiectasis,and bullous lung diseases.27. The method of embodiment 21, wherein the fibrotic diseases ofconnective tissue is selected from scleroderma, systemic sclerosis,generalized scleroderma, limited scleroderma and post-surgicaladhesions.28. The method of embodiment 21, wherein the disease or disorder isselected from muscular dystrophy, amyotrophic lateral sclerosis orchronic heart failure.29. A method for reducing the severity of delayed graft kidney functionin a patient that has received a kidney transplant, the methodcomprising administering to the patient the solid form of any one ofembodiments 1-12, the composition of any one of embodiment 13-16, or thepharmaceutical composition of embodiment 17 or 18.30. The method of embodiment 19, wherein the patient has received adeceased donor kidney.31. A method for preventing acute kidney injury after cardiac surgeryinvolving cardiopulmonary bypass, the method comprising administering toa patient the solid form of any one of embodiment 1-12, the compositionof any one of embodiment 13-16, or the pharmaceutical composition ofembodiment 17 or 18.32. A solid form of Compound 1 obtained by a process described herein.

EXAMPLES

The following examples are presented in order to more fully illustratethe preferred embodiments of the invention. They should in no way beconstrued, however, as limiting the broad scope of the invention.

Example 1: Synthesis of Compound 1

Unless otherwise indicated, starting materials are either commerciallyavailable or readily accessible through laboratory synthesis by anyonereasonably familiar with the art.

As described in WO 2004/058721, Compound 1 was synthesized according toScheme 1.

To a solution of diethoxyphosphorylacetaldehyde tosylhydrazone (3, 75 g)in 400 mL of THF was added 11.6 g of 60% NaH in portions, and thesolution was stirred for 15 min. The solution was cooled to 0° C., andthen a solution of 3-(2-thienyl)acrylaldehyde (2) in 100 mL THF wasadded dropwise. The reaction was then stirred at room temperature for 1hour, then at reflux for 1 hour. The reaction mixture was partitionedbetween 5% NaH₂PO₄ and ethyl acetate. The organic layer was separated,washed with water and brine, dried over magnesium sulfate, filtered andconcentrated to provide the crude title product as a brown oil.Purification via silica gel column chromatography afforded 8.3 g of ayellow powder. Trituration with dichloromethane/hexane afforded 4.4 g ofyellow powder having >98% purity: ¹H NMR (CDCl₃) δ 6.47 (d, 1H, J=1.5Hz), 6.93 (d, 1H, J=9.9 Hz), 6.99 (dd, 1H, J=3.9, 2.1 Hz), 7.06 (d, 1H,J=2.1 Hz), 7.20 (d, 1H, J=3.9 Hz), 7.22 (d, 1H, J=9.9 Hz), 7.57 (d, 1H,J=1.5 Hz).

The conversion of 3-arylacrylaldehydes into substituted pyrazoles viatreatment with diethoxyphosphorylacetaldehyde tosylhydrazone (8) isdescribed in the literature (Almirante, N., Cerri, A.; Fedrizzi, G.,Marazzi, G.; Santagostino, M. Tetrahedron Let. 1998, 39, 3287).3-(2-Thienyl)acrylaldehyde (2) was prepared from 2-thienaldehyde andacetaldehyde as described in Heskin, H., Miller, R. E., Nord, F. F. J.Org. Chem. 1951, 16, 199.

Example 2 Crystallization Screen of Compound

To a three-necked round bottom flask was added 100 mg of Compound and asuitable solvent. The resulting mixture was stirred at appropriatetemperature for 30 In certain cases, the reaction mixture became clearsolution. In these cases, the reaction mixture was cooled to anappropriate temperature. Crystal formation was observed in some cases.Crystals were collected by filtration and dried under vacuum at 25-30°C. to afford dry product. The results of the screen are summarized inTable 1.

TABLE 1 Results of crystallization screen of Compound 1. Clear Crystalsolution formation Solid Input Solvent observed started at Output YieldForm Entry Solvent of 1 Volume at (° C.) (° C.) (g) (%) Observed  1Methanol 3 g   6 mL 40-45  0 to −5 1.66 55.3 A  2 Ethanol 3 g  7.5 mL40-45 20-25 1.08 36.0 A  3 Acetone 3 g   6 mL 40-45 0-5 1 33.3 A  4Ethyl methyl Ketone 3 g   6 mL 40-45  0 to −5 0.72 24.0 A  5 Methylisobutyl ketone 3 g 16.5 mL 40-45  0 to −5 1.03 34.3 A  6 Acetonitrile 3g   21 mL 40-45 25-30 0.86 28.7 A  7 Propionitrile 3 g 13.5 mL 40-4515-20 1.4 46.7 A  8 Ethyl Acetate 3 g 13.5 mL 40-45 25-30 1.13 37.7 A  9Tetrahydrofuran (THF) 3 g  4.5 mL 40-45 0-5 0.7 23.3 A 10 1,4-Dioxane 3g 16.5 mL 40-45 0-5 0.58 19.3 A 11 2-Ethoxyethanol 3 g   6 mL 40-45 0-50.2 6.7 A 12 Ethanol/Acetic acid (9:1) 3 g   6 mL 40-45 0-5 1.46 48.7 A13 Acetone/Water (9:1) 3 g  4.5 mL 40-45 25-30 0.6 20.0 A 14 THF/Water(9:1) 3 g   3 mL 40-45 15-20 0.83 27.7 A 15 1,4-Dioxane/Water (9:1) 3 g 4.5 mL 40-45 10 to 15 0.86 28.7 A 16 Methanol/water (9:1) 3 g 10.5 mL40-45  5 to 10 1.25 41.7 A 17 Acetonitrile/water (9:1) 3 g   12 mL 40-4525-30 0.9 30.0 A 18 1-Butanol 3 g 19.5 mL 40-45 0 to 5 0.44 14.7 A 192-Butanol 3 g 22.5 mL 40-45  0 to −5 0 0 A 20 3-Methyl-1-butanol 3 g22.5 mL 40-45 0-5 1.02 34.0 A 21 2-Methyl-1-propanol 3 g   33 mL 40-450-5 1.15 38.3 A 22 Isopropanol 3 g   21 mL 40-45 0-5 0.5 16.7 A 23Isobutyl acetate 3 g 31.5 mL 40-45 10 to 15 1.62 54.0 A 24 Isopropylacetate 3 g 34.5 mL 40-45 10 to 15 1.05 35.0 A 25 Toluene 3 g  120 mL40-45 10 to 15 2.15 71.7 A 26 n-Butyl acetate 3 g   21 mL 40-45 0-5 1.446.7 A 27 Dichloromethane (DCM) 3 g   21 mL 40-45 0-5 2 66.7 A 28 Methyltert-butyl ether 3 g   60 mL 40-45 0-5 1.4 46.7 A  29^(a)Dimethylsulfoxide 3 g   3 mL 40-45 N/A 2.93 97.7 A (DMSO)  30^(b)Dimethylformamide 3 g   3 mL 38-40 N/A 2.97 99.0 A (DMF)  31^(a)DMSO/water (1:1) 3 g   3 mL 32 N/A — — A  32^(a) 2- 3 g  7.5 mL 40-45 5-10 — — A Methyltetrahydrofuran  33^(a) Ethanol/water (9:1) 3 g 10.5mL 40-45 15-20 — — A  34^(c) Acetic acid 3 g   30 mL 40-45 N/A 2.6 86.7A  35^(d) Glycerol in methyl 3 g  1.5 mL 40-45 −10 to −5  0.95 31.7 Aisobutyl ketone (MIBK) + 16.5 mL   (MIBK)  36^(e) Propylene glycol in 3g  1.5 mL 40-45 −50 to −60 1.78 59.3 A and C MIBK + 16.5 mL   (MIBK) 37^(e) Ethylene glycol in 3 g  1.5 mL 40-45 −50 to −60 1.89 63.0 A andD MIBK + 16.5 mL   (MIBK) ^(a)Solid not formed at 0-5° C. and at −40° C.Raised temperature to room temperature and added 12 mL water, Crystalformed and collected by filtration. ^(b)Solid not formed at 0-5° C. andat −60° C. Raised temperature to room temperature and added 12 mL water.Crystal formed and collected by filtration. ^(c)Solid not formed at roomtemperature. Added 12 mL water. Crystal formed and collected byfiltration. ^(d)Glycerol not miscible in MIBK. Heating needed.^(e)Heating needed.

As can be seen from the results disclosed in Table 1, Forms A, C, and Dof Compound 1 can be prepared under different conditions.

Example 3: Characterization of Solid Forms and Mixtures Thereof fromCrystallization Screen of Example 2

General Methods:

X-Ray Powder Diffraction (XRPD)

XRPD was performed with PANalytical X-ray diffractometer PW 1710, wherethe tube anode was Cu with Ka radiation. The pattern was collected instep scan mode (step size of 0.02° 20, counting time 2.4 s/step). Thesample was measured without any special treatment other than theapplication of slight pressure to get a flat surface. The measurementswere performed in an ambient air atmosphere.

Thermo Gravimetric—Fourier Transform Infrared (IG-FTIR) and ThermoGravimetric Analysis

The TG-FTIR instrument consists of a thermogravimetric analyzer (TG)coupled with a Fourier-Transform Infrared (FTIR) spectrometer for theanalysis of evolved gases such as H₂O. Samples were characterized bytheir mass loss combined with characterization of the evolvedcomponents. Thermo gravimetric measurements were carried out with aNetzsch Thermo-Microbalance TG 209 coupled to a Bruker FTIR SpectrometerVector 22. Sample pans with a pinhole were used under an N₂ atmosphere,at a heating rate of 10 K/min, with a temperature range of 25 to 250° C.Additional Thermo Gravimetric Analysis was conducted using a TAInstruments Q500 TGA under various conditions.

Differential Scanning Calorimetry (DSC)

Thermal analysis was carried out with a Perkin Elmer DSC7 with thefollowing experimental conditions: 3 to 6 mg sample mass, closed goldsample pan, temperature range from −50° C. to 120° C., and heating rate20 K/min. The samples were weighed in air or dry N₂ atmosphere.Additional thermal analysis was conducted using a TA Instruments Q1000DSC using hermetic aluminum pans under various conditions.

Filtration

During the following experiments: suspension equilibration,precipitation experiment, recrystallization, relative stabilityexperiments and water solubility experiment, a filtration step wasconducted. Centrifugal filter devices: Ultrafree-CL (0.22 μm),Millipore; Centrifuge type or Eppendorf 5804R were used at a temperatureof 22° C. and centrifugation program of 2 min 3000 rpm.

Form A

Form A was prepared under conditions described in Table 1. The XRPDpattern of Form A of Compound 1 is depicted in FIG. 1, and thecorresponding data are summarized below:

Degrees d-spacing Relative 2-Theta (Å) intensity (%) 8.60 10.27 23.115.61 5.67 1.0 17.22 5.15 19.3 17.30 5.12 100 17.35 5.11 58.2 21.04 4.224.4 22.05 4.03 1.5 23.41 3.80 2.6 24.97 3.56 2.4 25.63 3.47 2.1 26.103.41 1.8 35.06 2.56 2.3

TGA and DSC analysis were performed on 28 samples of Form A, preparedunder various conditions from Table 1. Table 2 summarizes the TGA andDSC data from these experiments.

FIG. 2 shows a representative differential scanning calorimeter (DSC)thermogram of Form A. FIG. 3 is another Representative DSC thermogram ofForm A, and FIG. 4. is a further representative DSC thermogram of FormA. FIG. 5 shows a representative thermogravimetric analysis (TGA) curveof Form A. FIG. 6 is another representative TGA curve of Form A. FIG. 7is a further representative TGA curve of Form A.

TABLE 2 DSC and TGA Analysis of Form A TGA (weight loss %) 0° C.- 100°C.- 150° C.- 200° C.- 250° C.- Entry Solvent 100° C. 150° C. 200° C.250° C. 300° C. DSC 1 Ethanol/Acetic acid   0.02% 0.035%   7.21%  65.67%— 119.58 (17:1) 2 Methanol 0.00002% 0.44%  8.74%  74.99%  99.87% 116.723 Ethanol   0.01% 0.35%  6..07%  70.00%  99.82% 116.42 4 Acetone   0.01%0.61%  9.14%  93.10%  99.80% 115.83 5 Ethyl methyl   0.01% 0.62%  8.94% 79.69%  99.79% 115.57 Ketone 6 Methyl isobutyl   0.03% 0.70% 13.22% 99.72%  99.76% 116.09 ketone 7 Acetonitrile   0.01% 0.48%  9.29% 85.35%  99.78% 116.24 8 Propionitrile  0.004% 0.51%  9.05%  94.02% 99.81% 116.23 9 Ethyl acetate  0.0006% 0.39%  7.67%  70.02%  99.92%115.62 10 Tetrahydrofuran   0.03% 0.96% 12.14%  98.73%  99.84% 116.47(THF) 11 Ethanol/Acetic acid   0.01% 0.73% 10.70%  93.42%  99.53% 115.63(9:1) 12 Acetone/Water (9:1)   0.01% 0.60% 10.44%  95.99%  99.80% 116.5413 THF/Water (9:1)   0.04% 0.78%  8.24%  72.70%  99.70% 116.35 141,4-Dioxane/Water   0.04% 0.98%  8.39%  77.43%  99.90% 115.45 15Methanol/Water   0.01% 0.47%  7.25%  66.81%  99.92% 116.50 (9:1) 16Acetonitrile/Water   0.04% 0.71% 12.80% 100.40%  99.98% 116.06 (9:1) 173-Methyl-1-butanol   0.18% 0.89%  9.74%  83.52% 100.30% 116.06 182-Methyl-1-propanol   0.05% 1.59% 23.05% 100.10% 100.20% 115.66 19Isopropanol   0.01% 0.46%  7.39%  65.74% 100.80% 115.65 20 Isobutylacetate   0.10% 0.75% 12.05%  99.49%  99.79% 116.87 21 Isopropyl acetate  0.01% 0.52%  9.20%  83.20%  99.70% 115.43 27 Toluene   0.02% 0.54% 7.69%  74.02%  99.84% 115.90 23 n-Butyl acetate   0.02% 0.51%  7.39% 64.49%  99.87% 116.27 24 Dichloromethane   0.03% 0.83%  7.69%  61.29% 99.980% 116.03 (DCM) 25 Methyl tert-butyl   0.11% 0.56%  8.44%  72.54%100.00% 116.12 ether 26 Dimethylsulfoxide   0.01% 0.75%  9.91%  87.39% 99.74% 115.47 (DMSO) 27 Dimethylformamide   0.14% 0.92% 13.29%  99.82% 99.87% 115.25 (DMF) 28 Acetic acid   0.06% 0.96% 12.68%  91.38%  99.75%115.83

Form A is stable for at least one year under storage conditions ofambient temperature/75% RH (Relative Humidity), ambient temperature/100%RH, 30° C./75% RH, and 50° C./0% RH.

Mixture of Form A and Form C

A mixture of Form A and Form C was prepared under conditions describedin Table 1. The XRPD pattern of the mixture of Form A and Form C ofCompound 1 is depicted in FIG. 8, and the corresponding data issummarized below:

Degrees d-spacing Relative 2-Theta (Å) intensity (%) 8.58 10.30 4.810.97 8.06 3.9 11.81 7.49 9.2 14.72 6.01 3.2 15.65 5.66 3.1 17.32 5.1218.5 17.41 5.09 14.4 17.70 5.00 2.5 18.61 4.76 2.3 19.02 4.66 17.3 19.274.60 2.7 21.20 4.19 100 22.09 4.02 3.6 22.97 3.87 22.2 23.60 3.77 3.124.92 3.57 3.2 25.59 3.48 4.0 26.20 3.40 6.9 27.65 3.22 5.2 30.42 2.942.5 31.07 2.88 10.2 35.33 2.54 2.3

TGA and DSC analysis were performed on a sample of the mixture of Form Aand Form C prepared using conditions from Table 1. In DSC, threeendotherms were observed at 68.70, 99.45, 209.44 (FIG. 9). As depictedin FIG. 10, the mixture showed in TGA a weight loss of 9.10% from 0°C.-100° C.; 18.16% from 100° C.-150° C.; 25.02% from 150° C.-200° C.;78.39% from 200° C.-250° C.; and 99.46% from 250° C.-300′C.

Mixture of Form A and Form D

A mixture of Form A and Form D was prepared under conditions describedin Table 1. The XRPD pattern of the mixture of Form A and Form D ofCompound 1 is depicted in FIG. 11, and the corresponding data issummarized below:

Degrees d-spacing Relative 2-Theta (Å) intensity (%) 8.69 10.17 24.39.99 8.85 2.0 11.08 7.98 60.8 12.34 7.17 11.0 15.12 5.85 4.1 16.15 5.482.7 17.38 5.10 100 17.62 5.03 11.5 18.08 4.90 4.9 18.67 4.75 6.1 19.474.55 5.9 21.13 4.20 34.3 21.60 4.11 84.7 22.2.2 4.00 74.5 22.76 3.90 2.023.50 3.78 7.6 23.91 3.72 34.4 25.04 3.55 11.7 25.69 3.46 16.8 26.493.36 5.5 28.36 3.14 5.0 28.52 3.13 8.2 29.98 2.98 5.5 30.60 2.92 5.531.84 2.81 7.0 33.83 2.65 2.6 34.44 2.60 2.0 35.74 2.51 2.8 38.77 2.321.0

TGA and DSC analysis was performed on a sample of the mixture of Form Aand Form D prepared using conditions from Table 1. In DSC, fourendotherms were observed at 89.95, 111.24, 123.52, and 223.02° C.,respectively (FIG. 12). As depicted in FIG. 13, the mixture showed inTGA a weight loss of 7.74% from 0° C.-100° C.; 23.72% from 100° C.-150°C.; 30.80% from 150° C.-200° C.; 79.68% from 200° C.-250° C.; and 99.32%from 250° C.-300° C.

Example 4: Scaled-Up Preparation and Characterization of Compound 1Solid Forms

General Methods:

X-Ray Powder Diffraction (RPD)

XRPD patterns of samples from scaled-up preparations were recorded atambient temperature on a Bruker D8 Advance X-ray diffractometer(Karlsruhe, Germany) using Cu Kα radiation (λ=1.54 Å) at 40 kV, 40 mApassing through a Vario monochromator (Karlsruhe, Germany). The samplewas loaded on a zero-background holder and gently pressed by a cleanglass slide to ensure co-planarity of the powder surface with thesurface of the holder. Data were collected in a continuous scan modewith a step size of 0.05 and dwell time of 1 s over an angular range of3° to 40° 2θ. Obtained diffractograms were analyzed with DIFFRAC.EVAdiffraction software (Bruker, Wis., USA).

In some cases, the X-ray intensity data were measured on a Bruker D8 Ecodiffractometer system equipped with a graphite monochromator and a Cu KαSealed tube (λ=1.54 Å). The sample was loaded in a polyimide capillariesand collected data in transmission mode. Bruker's APEX3 software suite(Bruker, Wis., USA) was used to collect and extract the intensity data.Obtained diffractograms were analyzed with TOPAS software (Bruker, Wis.,USA).

Mercury 4.2.0 software (Build 257471, Cambridge Crystallographic DataCentre, UK) was used to calculate the XRPD patterns from single crystaldata.

Thermogravimetric Analysis (TGA)

TGA was performed using a Discovery TGA 5500 (TA® Instruments, NewCastle, Del., USA) instrument operating with TRIOS software (Version5.0). The sample was placed in an aluminum pan. The sample cell waspurged with dry nitrogen at a flow rate of 15 mL/min. A heating rate of10° C./min from 25° C. to desired temperature was used in all theexperiments.

Differential Scanning Calorimetry (DSC)

Conventional DSC experiments were performed using a Discovery DSC 250(TA® Instruments, New Castle, Del., USA) instrument equipped with arefrigerated cooling system (RCS90) and operating with TRIOS software(Version 5.0). The sample cell was purged with dry nitrogen at a flowrate of 50 mL/min. Accurately weighed samples (2-5 mg) placed in TZeropans with a pin hole were scanned at a heating rate of 10° C./min over atemperature range of 25° C. to desired temperature was used in all theexperiments

Compound 1 Lot I

Compound 1 was provided in a form with an XRPD as shown in FIG. 14, aTGA as shown in FIG. 15, and a DSC as shown in FIG. 16. Herein, thismaterial is referred to as “Compound 1 Lot I.”

Form A

Compound 1 Form A was synthesized by recrystallizing Compound 1 Lot Ifrom methanol. In a typical reaction, ˜450 mg of Compound 1 Lot I wasdissolved in 2 mL of methanol while heating at 50° C. Resultant solutionwas kept at room temperature and allowed for slow evaporation of thesolvent. Crystals suitable for single crystal X-ray diffraction wereobtained within one day.

Compound 1 Form A bulk powder was prepared as follows: ˜5 g of Compound1 Lot I was suspended in 5 mL of methanol and slurried at roomtemperature for two days. The resulting solid was filtered using 0.45 μmPTFE syringe filter.

Single crystal X-ray diffraction of Compound 1 Form A was obtained (FIG.42A). Crystal data and structure refinement parameters are summarizedbelow:

Temperature (K)  278.15 Crystal system Monoclinic Space group C2/c a (Å)  2.5572(10) b (Å)   4.9949(2) c (Å)  16.8890(8) α (°)  90 β (°) 108.445(2) γ (°)  90 Volume (Å³) 1725.12(14)

The XRPD pattern of Compound 1 Form A calculated from single crystalX-ray diffraction data is shown in FIG. 17 and is summarized below:

2θ (°) d-spacing (Å) Intensity Counts (I) 8.64 10.22 1690 11.04 8.01422.5 11.67 7.57 88.3 16.06 5.51 380.0 17.34 5.11 9972 18.27 4.85 464.718.69 4.74 1532 19.49 4.55 387.5 20.66 4.30 587.9 21.09 4.21 3023 21.704.09 1257 22.10 4.02 5053 22.76 3.90 636.7 23.46 3.79 723.6 23.74 3.74238.5 25.06 3.55 6064 25.70 3.46 7656 26.12 3.41 301.6 26.32 3.38 352.727.64 3.23 147.8 27.78 3.21 140.2 28.31 3.15 2450 28.49 3.13 300.2 29.043.07 293.7 29.95 2.98 1525 31.59 2.83 197.4 31.82 2.81 125.7 32.25 2.77707.3 33.22 2.69 71.4 34.21 2.62 391.5 34.42 2.60 415.4 35.08 2.56 791.935.53 2.52 173.3 36.33 2.47 100.8 36.70 2.45 316.9 37.16 2.42 309.837.65 2.39 53.2 39.02 2.31 22.1 39.60 2.27 156.6 39.81 2.26 392.5

The XRPD pattern of Compound 1 Form A bulk powder is shown in FIG. 18.Comparison of observed XRPD pattern of Compound 1 Form A bulk powdercorresponds well with the calculated XRPD pattern (FIG. 17).

TGA of Compound 1 Form A is shown in FIG. 19. A weight loss of 0.6% wasobserved up to 150° C.

DSC of Compound 1 Form A is shown in FIG. 20. One endotherm was observedat 116.42° C.

A comparison of Compound 1 Lot I is shown in FIG. 21 and verifies thatCompound 1 Lot I matches Form A.

Form C

Compound 1 Form C was prepared as follows: ˜500 mg of Compound 1 Lot Iwas dissolved in a solvent mixture (250 μl of propylene glycol and 1500μl of methyl isobutyl ketone) while heating at 50° C. The resultantsolution was kept at −27° C. for 48 hours to yield Compound 1 Form C.Solids were collected by filtration using 0.45 μm PTFE syringe filter.

Single crystal X-ray diffraction of Compound 1 Form C was obtained andshowed that Compound 1 Form C is a propylene glycol solvate (2:1Compound 1:propylene glycol) (FIG. 42B). Crystal data and structurerefinement parameters are summarized below:

Temperature (K) 278.15 Crystal system Orthorhombic Space group Pbcn a(Å) 28.481(4) b (Å) 7.7056(9) c (Å) 10.1243(13) α (°) 90 β (°) 90 γ (°)90 Volume (Å³) 2221.9(5)

The XRPD pattern of Compound 1 Form C calculated from single crystalX-ray diffraction data is shown in FIG. 22 and is summarized below:

2θ (°) d-spacing (Å) Intensity Counts (I) 6.20 14.24 115.6 11.88 7.44816.6 12.41 7.13 31.7 14.79 5.99 645.4 15.72 5.63 294.4 17.50 5.06 149017.78 4.98 226.8 19.08 4.65 1725 19.36 4.58 327.8 21.28 4.17 10000 21.894.06 178.0 23.07 3.85 2644 23.69 3.75 338.2 23.92 3.72 68.5 24.70 3.60418.4 24.90 3.57 191.4 25.50 3.49 96.2 25.71 3.46 154.9 26.28 3.39 646.227.74 3.21 464.2 28.13 3.17 81.9 29.10 3.07 81.6 29.31 3.04 132.3 29.553.02 209.9 30.51 2.93 215.7 31.15 2.87 1058 31.76 2.82 67.2 32.93 2.7293.6 33.19 2.70 163.7 33.36 2.68 70.1 34.63 2.59 12.8 35.05 2.56 93.635.40 2.53 274.8 35.90 2.50 112.6 36.20 2.48 77.1 36.60 2.45 78.3 37.572.39 105.6 37.69 2.38 214.3 38.05 2.36 105.1 38.54 2.33 127.0 38.80 2.32124.8 39.05 2.30 155.2 39.46 2.28 50.0 39.82 2.26 34.2

The XRPD pattern of Compound 1 Form C collected from the scaled-uppreparation is shown in FIG. 23. Comparison of observed XRPD pattern ofCompound 1 Form C corresponds well with the calculated XRPD pattern(FIG. 22).

TGA of Compound 1 Form Cis shown in FIG. 24. A weight loss of 20.27% wasobserved up to 150° C. Observed weight loss correlated well withcalculated percentage of propylene glycol in crystal lattice based onsingle crystal X-ray diffraction (17.76%).

DSC of Compound 1 Form Cis shown in FIG. 25. One endotherm was observedat 75.22° C.

Form D

Compound 1 Form D was prepared as follows: −500 mg of Compound 1 Lot Iwas dissolved in a solvent mixture (250 μl of ethylene glycol and 1500μl of methyl isobutyl ketone) while heating at 50° C. The resultantsolution was kept at −27° C. for 48 hours to yield Compound 1 Form D.Solid was collected by filtration using 0.45 μm PTFE syringe filter.

Single crystal X-ray diffraction of Compound 1 Form D was obtained andshowed that Compound 1 Form D is a ethylene glycol solvate (2:1 Compound1:ethylene glycol) (FIG. 42C). Crystal data and structure refinementparameters are summarized below:

Temperature (K) 278.15 Crystal system Orthorhombic Space group Pbcn a(Å) 28.544(3) b (Å) 7.4452(8) c (Å) 9.8184(10) α (°) 90 β (°) 90 γ (°)90 Volume (Å³) 2086.6(4)

The XRPD pattern of Compound 1 Form D calculated from single crystalX-ray diffraction data is shown in FIG. 26 and is summarized below:

2θ (°) d-spacing (Å) Intensity Counts (I) 6.19 14.28 6185 12.28 7.201019 12.38 7.14 769.5 15.10 5.86 584.0 15.24 5.81 638.3 16.17 5.48 206.617.60 5.03 118.4 18.06 4.91 2066 18.63 4.76 175.5 19.11 4.64 56.9 19.444.56 774.4 20.35 4.36 51.4 21.58 4.11 10000 21.95 4.05 334.6 22.55 3.94349.9 23.88 3.72 3614 24.70 3.60 97.3 24.88 3.58 260.0 25.57 3.48 60.925.76 3.46 70.1 26.07 3.42 88.3 26.33 3.38 141.1 26.50 3.36 646.6 26.753.33 100.4 26.99 3.30 52.9 27.25 3.27 148.4 28.51 3.13 925.8 28.72 3.1194.2 29.96 2.98 44.2 30.10 2.97 72.2 30.26 2.95 54.3 30.47 2.93 305.530.62 2.92 204.7 30.75 2.90 119.6 31.27 2.86 69.2 31.57 2.83 62.0 31.832.81 617.8 31.97 2.80 259.2 32.38 2.76 59.6 32.67 2.74 83.2 33.61 2.66112.6 33.82 2.65 233.2 34.84 2.57 17.0 35.78 2.51 344.8 36.02 2.49 92.836.36 2.47 95.0 36.53 2.46 110.3 36.66 2.45 98.4 37.10 2.42 203.5 37.442.40 74.6 37.81 2.38 129.3 38.38 2.34 47.4 38.72 2.32 499.3 39.24 2.29300.7 39.78 2.26 61.9

The XRPD pattern of Compound 1 Form D collected from the scaled-uppreparation is shown in FIG. 27. Comparison of observed XRPD pattern ofCompound 1 Form D corresponds well with the calculated XRPD pattern(FIG. 26).

TGA of Compound 1 Form D is shown in FIG. 28. A weight loss of 16.46%was observed up to 150° C. Observed weight loss correlated well withcalculated percentage of ethylene glycol in crystal lattice based onsingle crystal X-ray diffraction (14.97%).

DSC of Compound 1 Form D is shown in FIG. 29. One endotherm was observedat 76.95° C.

Example 5: Dynamic Vapor Sorption of Compound 1 Solid Forms

Moisture sorption/desorption data were collected on a DVS-intrinsicvapor sorption analyzer (Surface Measurement Systems NA, Allentown, Pa.,USA) and operating with DVS-intrinsic control software (Version1.0.5.1). Samples were not dried prior to analysis. Sorption anddesorption data were collected over a range from 5% to 98% relativehumidity (RH) via 5% RH increments under a nitrogen purge. Theequilibrium criterion used for analysis was less than 0.005% weightchange in 10 min with a maximum equilibration time of 6 h.

DVS of Form A is shown in FIG. 30. Form A absorbed maximum of 0.47% evenat 98% RH, which confirms that Form A is non-hygroscopic. In addition nohysterisis is observed, which indicates the material did not changeform.

DVS of Form C is shown in FIG. 31. Form C exhibited weight loss of18.61% throughout the experiment and displayed indications of a possibleform change during the experiment. Weight loss observed in DVS closelymatches weight of volatile components present in Form C (17.76%).

DVS of Form D is shown in FIG. 32. Form D exhibited weight loss of15.69% observed throughout the experiment and displayed indications of apossible form change during the experiment. Weight loss observed in DVSclosely matches weight of volatile components present in Form D(14.97%).

XRPD was collected on the materials recovered after the dynamic moisturesorption experiments described above. As can be seen in FIG. 33, Form Aexhibited no change during the experiment, while Form C and Form Dconverted to Form A during the experiment. This data suggest that Form Ais more stable compared to Form C and Form D and that no special storageconditions, particularly with respect to moisture, are required for FormA.

Example 6: Slurry and Competitive Slurry Experiments

Slurry and competitive slurry experiments were performed to determinethe relative stability of Compound 1 solid forms. In a typicalexperiment, excess of a Compound 1 solid form or mixture thereof wassuspended in isopropyl alcohol and stirred at room temperature for 72hours. Resulting suspensions were filtered using a 0.45 μm PTFE syringefilter to isolate the solids. Solids were then analyzed by XRPD. XRPDresults are summarized in FIG. 34 and FIG. 35. Results of slurry andcompetitive slurry experiments are summarized below:

Starting Material(s) Resultant Material Form A Form A Form C Form A FormD Form A Form A and Form C Form A Form A and Form D Form A Form C andForm D Form A

Example 7: Solid State Stability of Compound 1 Solid Forms

Solid state stability of Compound 1 solid forms was assessed by storingsamples of each solid form at 2-8° C., 25° C./60% RH and 40° C./75% RH.Samples were taken after 1 week, 2 weeks, 3 weeks, and 4 weeks, and XRPDwas collected. FIG. 36, FIG. 37, and FIG. 38 shows XRPD data after 4weeks for each form under each condition. Results of solid statestability studies are summarized below:

Results after: Starting Form 1 week 2 weeks 3 weeks 4 weeks Form A 2-8°C. Form A Form A Form A Form A 25° C./60% RH Form A Form A Form A Form A40° C./75% RH Form A Form A Form A Form A Form C 2-8° C. Form C Form CForm C Form C 25° C./60% RH Form C Form C Form C Form A 40° C./75% RHForm A Form A Form A Form A Form D 2-8° C. Form D Form D Form D Form D25° C./60% RH Form A + D Form A + D Form A + D Form A + D 40° C./75% RHForm A Form A Form A Form A

Example 8: UV Stability of Compound 1 Solid Forms

UV stability of Compound 1 solid forms was assessed by placing thesamples in a dark sealed box at room temperature under UV lamps (4watts, ˜2 cm distances from the sample). Stability was assessed at twodifferent wavelengths (254 nm and 365 nm). Samples were taken after 1week, 2 weeks, 3 weeks, and 4 weeks, and XRPD and UPLC-MS werecollected. FIG. 39, FIG. 40, and FIG. 41 shows XRPD results after 1 weekfor each form under each condition. Results are summarized below:

Starting Results after: Material 1 week 2 weeks 3 weeks 4 weeks Form A254 nm Form A (100% Form A (100% Form A (100% Form A (100% purity)purity) purity) purity) 365 nm Form A (100% Form A (100% Form A (100%Form A (100% purity) purity) purity) purity) Form C 254 nm Form C (100%Form C (100% Form C + A NA purity) purity) (100% purity) 365 nm Form C(100% NC (67% NC (56% NC (51% purity) purity) purity) purity) Form D 254nm Form D (100% Form D (100% Form D (100% Form D (100% purity) purity)purity) purity) 365 nm Form D (100% NC (65% NC (63% NC (61% purity)purity) purity) purity) *NC: XRPD not collected due to low chemicalpurity as assessed by UPLC-MS; NA: Not availableAccording to data shown above, Form A of Compound 1 shows greaterstability than other forms under two different UV wavelengths (254 nmand 365 nm, respectively). This is particularly true under longer UVwavelength, i.e., 365 nm.

Example 9: Stability Studies of Solid Forms of Compound 1 at DifferentTemperatures

Twenty mg each of Compound 1 Form A, Form C, and Form D were stored at4° C., 22° C., and 50° C., protected from light. At specified timepoints, the purities of samples were monitored using UPLC-MS. Nosignificant degradation of Compound 1 was observed, though changes inform would not be detected using this method. The results are shownbelow:

Purity at 4° C.: Purity, % Date Form A Form C Form D Day 1 100 100 100Day 15 100 100 100 Day 30 100 100 100

Purity at 22° C.: Purity, % Date Form A Form C Form D Day 1 100 100 100Day 15 100 100 100 Day 30 100 100 100

Purity at 50° C.: Purity, % Date Form A Form C Form D Day 1 100 100 100Day 15 100 100 100 Day 30 100 100 100The above data show that Compound 1 are stable under short-term storageat 40° C., 22° C., and 50° C., regardless of form.

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A crystalline solid form of Compound 1:

wherein the solid form is characterized by one or more peaks in itsX-ray powder diffraction pattern (XRPD) selected from those at about8.64, about 11.04, about 17.34, about 25.06, and about 25.70 degrees2-theta.
 2. The solid form of claim 1, wherein the solid form ischaracterized by peaks in its XRPD at about 8.64, about 11.04, about17.34, about 25.06, and about 25.70 degrees 2-theta.
 3. The solid formof claim 1, wherein the solid form is characterized by substantially allof the peaks in its XRPD pattern at about: Degrees 2-Theta 8.64 11.0411.67 16.06 17.34 18.27 18.69 19.49 20.66 21.09 21.70 22.10 22.76 23.4623.74 25.06 25.70 26.12 26.32 27.64 27.78 28.31 28.49 29.04 29.95 31.5931.82 32.25 33.22 34.21 34.42 35.08 35.53 36.33 36.70 37.16 37.65 39.0239.60 39.81.


4. The solid form of claim 1, wherein the solid form is characterized bya weight loss of about 0.6% up to 150° C. using thermogravimetricanalysis.
 5. The solid form of claim 1, wherein the solid form ischaracterized by an endotherm at about 116.42° C. using differentialscanning calorimetry.
 6. A crystalline solid form of Compound 1:

wherein the solid form is a propylene glycol solvate characterized byone or more peaks in its XRPD pattern selected from those at about11.88, about 17.50, about 19.08, about 21.28, and about 23.07 degrees2-theta.
 7. The solid form of claim 6, wherein the solid form ischaracterized by peaks in its XRPD pattern at about 11.88, about 17.50,about 19.08, about 21.28, and about 23.07 degrees 2-theta.
 8. The solidform of claim 6, wherein the solid form is characterized bysubstantially all of the peaks in its XRPD pattern at about: Degrees2-Theta 6.20 11.88 12.41 14.79 15.72 17.50 17.78 19.08 19.36 21.28 21.8923.07 23.69 23.92 24.70 24.90 25.50 25.71 26.28 27.74 28.13 29.10 29.3129.55 30.51 31.15 31.76 32.93 33.19 33.36 34.63 35.05 35.40 35.90 36.2036.60 37.57 37.69 38.05 38.54 38.80 39.05 39.46 39.82.


9. The solid form of claim 6, wherein the solid form is characterized bya weight loss of about 20.27% up to 150° C. using thermogravimetricanalysis.
 10. The solid form of claim 6, wherein the solid form ischaracterized by an endotherm at about 75.22° C. using differentialscanning calorimetry.
 11. A crystalline solid form of Compound 1:

wherein the solid form is an ethylene glycol solvate characterized byone or more peaks in its XRPD pattern selected from those at about12.28, about 15.10, about 18.06, about 21.58, and about 23.88 degrees2-theta.
 12. The solid form of claim 11, wherein the solid form ischaracterized by peaks in its XRPD pattern at about 12.28, about 15.10,about 18.06, about 21.58, and about 23.88 degrees 2-theta.
 13. The solidform of claim 11, wherein the solid form is characterized bysubstantially all of the peaks in its XRPD pattern at about: Degrees2-Theta 6.19 12.28 12.38 15.10 15.24 16.17 17.60 18.06 18.63 19.11 19.4420.35 21.58 21.95 22.55 23.88 24.70 24.88 25.57 25.76 26.07 26.33 26.5026.75 26.99 27.25 28.51 28.72 29.96 30.10 30.26 30.47 30.62 30.75 31.2731.57 31.83 31.97 32.38 32.67 33.61 33.82 34.84 35.78 36.02 36.36 36.5336.66 37.10 37.44 37.81 38.38 38.72 39.24 39.78.


14. The solid form of claim 11, wherein the solid form is characterizedby a weight loss of about 16.46% up to 150° C. using thermogravimetricanalysis.
 15. The solid form of claim 11, wherein the solid form ischaracterized by an endotherm at about 76.95° C. using differentialscanning calorimetry.
 16. The solid form of claim 3, wherein the solidform is characterized by a weight loss of about 0.6% up to 150° C. usingthermogravimetric analysis.
 17. The solid form of claim 3, wherein thesolid form is characterized by an endotherm at about 116.42° C. usingdifferential scanning calorimetry.
 18. The solid form of claim 1,wherein the solid form is characterized by peaks in its X-ray powderdiffraction pattern at about 8.64, about 11.04, about 17.34, about25.06, and about 25.70 degrees 2-theta, corresponding to d-spacing ofabout 10.22, about 8.01, about 5.11, about 3.55, and about 3.46angstroms.
 19. The solid form of claim 1, wherein the solid form ischaracterized by substantially all of the peaks in its XRPD pattern atabout, corresponding to d-spacing of: Degrees 2-Theta d-spacing (Å) 8.6410.22 11.04 8.01 11.67 7.57 16.06 5.51 17.34 5.11 18.27 4.85 18.69 4.7419.49 4.55 20.66 4.30 21.09 4.21 21.70 4.09 22.10 4.02 22.76 3.90 23.463.79 23.74 3.74 25.06 3.55 25.70 3.46 26.12 3.41 26.32 3.38 27.64 3.2327.78 3.21 28.31 3.15 28.49 3.13 29.04 3.07 29.95 2.98 31.59 2.83 31.822.81 32.25 2.77 33.22 2.69 34.21 2.62 34.42 2.60 35.08 2.56 35.53 2.5236.33 2.47 36.70 2.45 37.16 2.42 37.65 2.39 39.02 2.31 39.60 2.27 39.812.26.